Pyridazinone compounds and uses thereof

Abstract

Disclosed herein are substituted pyridazinone compounds, conjugates, and pharmaceutical compositions for treating neuromuscular diseases such as Duchenne Muscular Dystrophy (DMD). The disclosed compounds are particularly useful for treating DMD and modulating the inflammatory inhibitors IL-1, IL-6, or TNF-alpha.

Description

[0001] CROSS-REFERENCE

[0002] This application claims the benefit of U.S. provisional application serial number 62 / 756,552, filed November 6, 2018, which is incorporated by reference in its entirety. BACKGROUND

[0003] Skeletal muscle is the largest organ system in the human body and has two main roles. The first is force generation to make muscles contract, move, and hold posture; the second is glucose, fatty acid, and amino acid metabolism. Skeletal muscle contraction during daily activities and exercise is naturally associated with muscle stress, breakdown, and remodeling, which is essential for muscle adaptation. In individuals with neuromuscular conditions such as Duchenne Muscular Dystrophy (DMD), muscle contraction leads to successive rounds of amplified muscle breakdown that the body struggles to repair. Eventually, as the patient ages, pathophysiological processes develop in the muscle that lead to excessive inflammation, fibrosis, and accumulation of fat deposits, heralding a sharp decline in body function and leading to death.

[0004] DMD is a genetic disease affecting skeletal muscle that is characterized by progressive muscle degeneration and weakness. There remains a need for treatments that reduce muscle breakdown in patients with neuromuscular conditions such as DMD. SUMMARY

[0005] The present disclosure relates generally to substituted pyridazinone compounds or salts of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II’), or (Ila), and pharmaceutical compositions thereof. The substituted pyridazinone compounds or salts of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II’), or (Ila) disclosed herein are useful for treating or preventing neuromuscular diseases. In some embodiments, the compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II’), or (Ila) is an inhibitor of skeletal muscle contraction. In some embodiments, the compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II’), or (Ila) is an inhibitor of myosin. In some embodiments, the compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II’), or (Ila) is an inhibitor of skeletal muscle myosin II.

[0006] In certain embodiments, the present disclosure provides a method of treating activity-induced muscle injury comprising administering to a subject in need thereof a compound or salt of any one of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), (IIa), (III), or (III’). In certain embodiments, the subject in need of treatment has a neuromuscular condition or a movement disorder. Examples of neuromuscular conditions include Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb girdle muscular dystrophy, tendonitis, and carpal tunnel syndrome. In some embodiments, the movement disorder comprises muscle spasticity. In some embodiments, the muscle spasticity can be selected from spasticity associated with multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, or cerebral palsy, or injury, or a traumatic event such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis.

[0007] The present disclosure provides compounds and salts thereof for use in the treatment of a disease. In certain aspects, the present disclosure provides compounds of Formula (I), (la), (lb), (Ic), (Id), (II), (II’), or (IIa), pharmaceutical compositions thereof, and methods for treating a disease.

[0008] In certain aspects, the present disclosure provides a compound represented by the structure of Formula (I):

[0009]

[0010] or a salt thereof, wherein:

[0011] each X is independently selected from C(R 3 ), N, and N + (-O - ), wherein at least one X is N or N + (-O - );

[0012] A is selected from -O-, -NR 4 -, -CR 5 R 6 -, -C(O)-, -S-, -S(O)-, and -S(O)2-;

[0013] R 1 is selected from:

[0014] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each is optionally substituted with one or more groups independently selected from halogen, -OR 10 , -SR10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0015] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 Substituents of -CN and -CN; or

[0016] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9substituted; or R 1 together form a 3- to 10-membered heterocycle or a saturated C 5 ring, wherein the 3- to 10-membered heterocycle or saturated C 3-10 ring is optionally substituted with one or more R 3-10 ; and 9 substituted; or R 1 together form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more R 4 ; and 9 ;

[0017] when A is -NR 4 -, R 1 is additionally selected from hydrogen, and when A is -C(O)-, R 1 is additionally selected from -N(R 10 )2and -OR 10 ;

[0018] each R 2 is independently selected from:

[0019] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2and -CN;

[0020] C 1-3 alkyl, C 2-3 alkenyl and C 2-3 alkynyl, wherein each is optionally substituted with one or more independently selected halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 ;)C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 Substituents of -CN and -CN; and

[0021] C 3-10 The carbon ring, optionally substituted by one or more substituents independently selected from: halogen, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN;

[0022] R 3 R 5 and R 6 Each is selected independently from:

[0023] Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and

[0024] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0025] R 3 With R 1Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 5 With R 1 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced;

[0026] R 4 Selected independently from:

[0027] Hydrogen; and

[0028] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0029] R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced;

[0030] R 7 and R 8 Selected independently from:

[0031] Halogen, -OR 10 -SR 10 -N(R) 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F and optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 2. C replaced by substituents of -NO2 and -CN 2-6 alkyl;

[0032] Each R 9 Selected independently from:

[0033] Halogen, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R)10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; and

[0034] C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 Substituents of -CN and -CN are used;

[0035] Each R 10 Selected independently from:

[0036] hydrogen;

[0037] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and

[0038] C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0039] n is 0, 1, or 2;

[0040] p is 0, 1, or 2; and

[0041] q is 1, 2, 3, 4 or 5, and when R 1 If it is not –CH3, q is further selected from 0.

[0042] In some respects, this disclosure provides compounds represented by the structure of formula (II):

[0043]

[0044] or its salt, wherein:

[0045] T is selected from -O-, -NR 14 -、-CR 15 R 16 -、-C(O)-、-S-、-S(O)- and -S(O)2;

[0046] R 11 Selected from:

[0047] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, each of which is independently selected from one or more halogens, -OR 20 -SR 20 -N(R) 20 )2、-C(O)R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-OC(O)N(R 20 )2、-N(R 20)C(O)OR 20 -C(O)OR 20 -OC(O)R 20 -S(O)R 20 -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), –CN, C 3-5 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced;

[0048] And C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -OR 20 -SR 20 -N(R) 20 )2、-C(O)R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-OC(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -C(O)OR 20 -OC(O)R 20 -S(O)R 20 -S(O)2R 20 , -NO2, =O, =S, =N(R 20 Substituents of -CN and -CN; or

[0049] R 11 With R 15 Together they form 3 to 10-membered heterocycles or C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 19 Replaced; or R 11 With R 14 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 19 Replaced;

[0050] When T is -NR 14 - At that time, R 11 Additionally, it is selected from hydrogen, and when T is -C(O)-, R 11 Additionally selected from -N(R)20 )2 and -OR 20 ;

[0051] Each R 12 Selected independently from:

[0052] Halogen, -OR 20 -SR 20 -N(R) 20 )2、-C(O)R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)N(R 20 )2、-OC(O)N(R 20 2. C(O)OR 20 -OC(O)R 20 -S(O)R 20 -S(O)2R 20 -NO2 and -CN;

[0053] C 1-3 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2、-C(O)R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -C(O)OR 20 -N(R) 20 )C(O)N(R 20 )2、-OC(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -OC(O)R 20 -S(O)R 20 -S(O)2R 20 , -NO2, =O, =S, =N(R 20 Substituents of -CN and -CN; and

[0054] C 3-10 A carbon ring, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2、-C(O)R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -N(R) 20)C(O)N(R 20 )2、-OC(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -C(O)OR 20 -OC(O)R 20 -S(O)R 20 -S(O)2R 20 , -NO2, =O, =S, =N(R 20 Substituents of -CN and -CN are used;

[0055] R 14 Selected independently from:

[0056] Hydrogen; and

[0057] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN; or

[0058] R 14 With R 11 Together they form a 3- to 5-membered heterocycle, which is optionally separated by one or more R 19 Replaced;

[0059] R 15 With R 11 Together they form saturated C 3-10 A carbon ring or a 3- to 10-membered heterocycle, optionally separated by one or more R... 19 Replaced;

[0060] R 16 Selected independently from:

[0061] Hydrogen, halogen, -OR 20 -SR 20 -N(R) 20 )2, -NO2, -CN and optionally selected independently by one or more halogens, -OR 20 -SR 20 -N(R) 20 2. C replaced by substituents of -NO2 and -CN 1-6 alkyl;

[0062] R 18 Selected independently from:

[0063] Halogen, -SR 20 -N(R) 202. -NO2 and optionally one or more independently selected from halogens, -OR 20 -SR 20 -N(R) 20 2. C replaced by substituents of -NO2 and -CN 2-6 alkyl

[0064] R 19 Selected independently from:

[0065] Halogen, -OR 20 -SR 20 -N(R) 20 )2、-C(O)R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-OC(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -C(O)OR 20 -OC(O)R 20 -S(O)R 20 -S(O)2R 20 , -NO2, =O, =S, =N(R 10 ) and -CN; and

[0066] C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 20 -SR 20 -N(R) 20 )2、-C(O)R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-OC(O)N(R 20 )2、-N(R 20 )C(O)OR 20 ,-C(O)OR 20 -OC(O)R 20 -S(O)R 20 -S(O)2R 20 , -NO2, =O, =S, =N(R 20substituted with one or more substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -NO2, -NH2, =O, =S, -O-C1-C6alkyl, -S-C1-C6alkyl, -N(C1-C6alkyl)2, -NH(C1-C6alkyl), C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10carbocycle, and 3- to 10-membered heterocycle;

[0067] each R 20 is independently selected from the group consisting of:

[0068] hydrogen;

[0069] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each is optionally substituted with one or more substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle, and 3- to 10-membered heterocycle;

[0070] C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each is optionally substituted with one or more substituents independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and haloalkyl;

[0071] z is 0, 1, or 2; and

[0072] v is 1, 2, 3, 4, or 5.

[0073] In certain aspects, the present disclosure provides a method of treating an activity-induced muscle injury comprising administering to a subject in need thereof a compound or salt of Formula (III):

[0074]

[0075] or a salt thereof, wherein:

[0076] each Y is independently selected from the group consisting of C(R 3 ), N, and N + (-O - );

[0077] A is absent or selected from the group consisting of -O-, -NR 4 -, -CR 5 R6 -, -C(O)-, -S-, -S(O)-, and -S(O)2-;

[0078] R 1 is selected from:

[0079] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 carbon ring, and 3- to 10-membered heterocycle, wherein each of said C 3-10 carbon ring and 3- to 10-membered heterocycle is optionally substituted with one or more R 9 ; and

[0080] C 3-10 carbon ring and 3- to 10-membered heterocycle, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10-S(O)2R 10 , -NO2, =O, =S, =N(R 10 Substituents of -CN and -CN; or

[0081] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced; and

[0082] When A is -NR 4 - At that time, R 1 Additionally, it is selected from hydrogen, and when A is -C(O)-, R 1 Additionally selected from -N(R) 10 )2 and -OR 10 ;

[0083] When A does not exist, R 1 Further selection from halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 -NO2 and –CN;

[0084] Each R 2 Selected independently from:

[0085] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, and -CN;

[0086] C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and

[0087] C 3-10 carbocyclyl, optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN

[0088] Each R 3 R 5 and R 6 Selected independently from:

[0089] Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0090] R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 5 With R 1 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced;

[0091] R 4 Selected independently from:

[0092] Hydrogen; and

[0093] C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0094] R 4 With R 1 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 9 Replaced;

[0095] Each R 7 and R 8 Selected independently from:

[0096] Halogen, -OR 10 -SR 10 -N(R) 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F and optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 2. C replaced by substituents of -NO2 and -CN 2-6 alkyl;

[0097] Each R 9 Selected independently from:

[0098] Halogen, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; and

[0099] C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN;

[0100] each R 10 is independently selected from:

[0101] hydrogen;

[0102] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle, and 3- to 10-membered heterocycle; and

[0103] C 3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and C 1-6 haloalkyl;

[0104] R 30 and R 31 are independently selected from R 10 or R 30 and R 31 together form C 3-7carbocyclic or 3- to 7-membered heterocyclic ring, wherein C 3-7 carbocyclic and 3- to 7-membered heterocyclic ring are optionally substituted with one or more substituents independently selected from R 9

[0105] n is 0, 1, or 2;

[0106] p is 0, 1, or 2; and q is 0, 1, 2, 3, 4, or 5.

[0107] In certain aspects, the present disclosure provides a method of treating a neuromuscular condition or treating activity-induced muscle damage or inhibiting muscle myosin II comprising administering to a subject in need thereof a compound or salt of any one of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), or (Ila).

[0108] In certain aspects, the present disclosure provides a method of treating a movement disorder comprising administering to a subject in need thereof a compound or salt of any one of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), or (Ila).

[0109] In certain aspects, the present disclosure provides a pharmaceutical composition comprising a compound or salt of any one of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), or (Ila) and a pharmaceutically acceptable excipient.

[0110] INCORPORATION BY REFERENCE

[0111] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF DRAWINGS

[0112] The novel features of the application are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present application will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the application are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0113] FIG. 1 depicts over-contraction-induced injury, which precedes inflammation and irreversible fibrosis, a hallmark of late-stage DMD pathology;

[0114] FIG. 2 N-benzyl-p-tolyl-sulfonamide (BTS), an inhibitor of fast fiber skeletal muscle myosin, has been shown to protect muscle from pathological muscle disorder in DMD zebrafish model embryos;​

[0115] FIG. 3 The reduction of pre-damage force at 100 Hz is depicted using an exemplary compound of this disclosure, compound 5.

[0116] FIG. 4 The following describes the post-damage force reduction at 175 Hz using an exemplary compound, compound 5, of the present disclosure.

[0117] FIG. 5 The intermediate elongation force decrease is depicted using the exemplary compound 5 of this disclosure;

[0118] FIG. 6 An increase in TA mass after damage is depicted using the exemplary compound 5 of this disclosure. Detailed Implementation

[0119] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, modifications, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in carrying out the invention. The scope of the invention is intended to be defined by the appended claims, thereby encompassing the methods and structures and their equivalents within the scope of those claims.

[0120] In some respects, this disclosure provides a method for treating neuromuscular diseases by selectively inhibiting skeletal muscle fast-twitch fibromyosin. In particular, the methods of this disclosure can be used to treat DMD and other neuromuscular diseases.

[0121] Skeletal muscle is primarily composed of two types of fibers: slow-twitch fibers (Type I) and fast-twitch fibers (Type II). In each muscle, these two types of fibers are arranged in a mosaic pattern, and the composition varies between different muscles and at different points in growth and development. Slow-twitch fibers have excellent aerobic energy production capacity. They have a low contraction rate but high fatigue tolerance. Slow-twitch fibers typically have higher mitochondrial and myoglobin concentrations than fast-twitch fibers and are surrounded by more capillaries. Due to lower myosin ATPase activity, slow-twitch fibers contract more slowly and produce less energy compared to fast-twitch fibers, but they can maintain contractile function for longer periods, such as in stability, postural control, and endurance training.

[0122] Human fast-twitch muscle fibers can be further divided into two main fiber types (Type Ila, Type IIx / d) based on the specific skeletal muscle fast myosin myosin they express. A third class of fast muscle fibers (Type lib) exists in other mammals, but is rarely found in human muscle. Fast-twitch muscle fibers have superior anaerobic energy production capacity and are capable of generating large amounts of tension in a short period of time. Generally, fast-twitch muscle fibers have lower concentrations of mitochondria, myoglobin, and capillaries than slow-twitch muscle fibers, and thus fatigue more quickly. Fast-twitch muscle fibers produce the strength and faster forces needed to resist activity.

[0123] The proportion of Type I and Type II can vary among different individuals. For example, in a non-athletic individual, each muscle fiber type can comprise nearly 50%. A strength athlete can have a higher proportion of fast-twitch muscle fibers, for example, 70-75% Type II in a sprinter. An endurance athlete can have a higher proportion of slow-twitch muscle fibers, for example, 70-80% slow-twitch muscle fibers in a long-distance runner. The proportion of Type I and Type II fibers can also vary according to the age of the individual. The proportion of Type II fibers, particularly Type IIx, can decrease with age in an individual, leading to loss of lean muscle mass.

[0124] Contraction of skeletal muscle results in muscle damage in subjects with neuromuscular diseases such as DMD, which appears to be more prevalent in fast muscle fibers. It has been observed that in a dystrophic mouse model, acute force loss after a strain injury was greater in a model of fast Type II fiber muscle than in a model of slow Type I fiber muscle (i.e., the soleus muscle). It has also been demonstrated that in a dystrophic mouse model, the degree of acute force loss and histological damage was directly proportional to peak force development during a strain. FIG. 1 Damage from over-contraction is shown, which occurs prior to inflammation and irreversible fibrosis characteristic of late-stage DMD pathology. [Figure adapted from: Claflin and Brooks, Am J Physiol Cell, 2008]. By limiting peak force production of Type II fibers and possibly increasing reliance on healthier Type I fibers, contraction-induced muscle damage in these patients can be reduced. N-benzyl-p-tolylsulfonamide (BTS) is an inhibitor of skeletal muscle fast myosin myosin, which has been shown to protect muscle from pathological muscle disorder in embryos from a DMD zebrafish model. [Source: Li and Arner, PLoS ONE, 2015]. FIG. 2

[0125] ​Skeletal muscle myosin inhibitors that are not selective for Type II fibers can result in undesirable inhibition of skeletal muscle contraction, including respiratory function and undesirable inhibition of heart activity, as the heart shares multiple structural components (e.g., Type I myosin) with skeletal muscle fibers of Type I. While not wishing to be bound by a particular mechanistic theory, the present disclosure provides selective inhibitors of skeletal muscle fast fiber myosin as a therapeutic option for DMD and other neuromuscular diseases. Targeted inhibition of Type II skeletal muscle myosin can reduce skeletal muscle contraction while minimizing impact on a subject’s daily activities.

[0126] Definitions

[0127] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0128] As used in the specification and claims, the singular form “a,” “an” and “the” include plural references unless the context clearly dictates otherwise.

[0129] The term “C x-y ” or “C x -C y ” when used with a chemical moiety such as alkyl, alkenyl or alkynyl is intended to include groups containing from x to y carbons in the chain. For example, the term “C 1-6 alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight chain alkyl and branched alkyl groups containing from 1 to 6 carbons.

[0130] The terms “C x-y alkenyl” and “C x-y alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups, which are similar to alkyl groups described above in terms of length and possible substitution, but which contain at least one double or triple bond, respectively.

[0131] The term "carbocycle" as used herein refers to a saturated, unsaturated, or aromatic ring wherein each ring atom is carbon. Carbocycles include 3- to 10-membered monocyclic, 5- to 12-membered bicyclic, 5- to 12-membered spirobicyclic, and 5- to 12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. In exemplary embodiments, an aromatic ring, e.g., phenyl, can be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Bicyclic carbocycles include any combination of saturated, unsaturated, and aromatic rings, where valency permits. Bicyclic carbocycles also include spirobicyclic rings, such as spiropentane. Bicyclic carbocycles include any combination of ring sizes, such as 3-3 spiro ring systems, 4-4 spiro ring systems, 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, naphthyl, and bicyclo[l.l.l]pentanyl.

[0132] The term "aryl" refers to an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system. An aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon and 5-18 carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p-electron system according to Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetrahydronaphthalene, and naphthalene.

[0133] The term "cycloalkyl" refers to a saturated ring wherein each ring atom is carbon. Cycloalkyl can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic, 5- to 12-membered bicyclic, 5- to 12-membered spirobicyclic, and 5- to 12-membered bridged rings. In certain embodiments, cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, cycloalkyl contains 5 to 7 carbon atoms. Cycloalkyl can be attached to the rest of the molecule through a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic carbocyclyl groups include, for example, adamantyl, spiropentane, norbornyl (i.e., bicyclo[2.2.1]heptyl), decalinyl, 7,7-dimethylbicyclo[2.2.1]heptyl, bicyclo[l.l.l]pentanyl, and the like.

[0134] The term "cycloalkenyl" refers to a saturated ring wherein each ring atom is carbon and there is at least one double bond between two ring carbons. Cycloalkenyl can include monocyclic and polycyclic rings, such as 3- to 10-membered monocyclic, 6- to 12-membered bicyclic, and 5- to 12-membered bridged rings. In other embodiments, cycloalkenyl contains 5 to 7 carbon atoms. Cycloalkenyl can be attached to the rest of the molecule through a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0135] The term "halo" or "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0136] The term "haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2- trifluoroethyl, 1-chloromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the haloalkyl group is optionally further substituted as described herein.

[0137] The term "heterocycle" as used herein refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclic, 6- to 12-membered bicyclic, 5- to 12-membered spiro, and 5- to 12-membered bridged rings. Bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic rings, where valence permits. In exemplary embodiments, an aromatic ring, for example, pyridyl, can be fused to a saturated or unsaturated ring, for example, cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene. Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles also include spirobicycles, for example, 5- to 12-membered spirocycles, such as 2-oxa-6-azaspiro[3.3]heptane.

[0138] The term "heteroaryl" refers to a radical derived from a 5- to 18-membered aromatic ring group containing 2 to 17 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) p-electron system according to Hückel theory. Heteroaryl groups include fused or bridged ring systems. The heteroatoms in a heteroaryl group are optionally oxidized. If there is one or more nitrogen atoms, they are optionally quaternized. Heteroaryl groups are attached to the rest of the molecule through any atom within the ring. Examples of heteroaryl groups include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzoindolyl, 1,3-benzodioxolanyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzodioxolanyl, benzodioxolyl, benzooxazonyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzodioxolyl, 2,3-benzodioxolyl, 2,3-dihydrobenzofuryl, carbazolyl, carbolinyl, cinnolinyl, decahydroquinolinyl, dioxolanyl, dioxolyl, furanyl, furazanyl, imidazolyl, imidazolinyl, imidazolidinyl, indazolyl, indazolinyl, indazolidinyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, octahydroquinolinyl, 2-oxa-6-azaspiro[3.3]heptanyl, oxazolyl, phenazinyl, phenarsenyl, phenazinyl, phenothiazinyl, phenoxazinyl, phenylazinyl, phthalazinyl, pteridinyl, purinyl, quinuclidinyl, quinoxalinyl, quinoxalinyl, quinazolinyl, quinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and xanthenyl groups. ​benzo[d]oxazolyl, benzoxazinyl, benzoxazinonyl, benzoxazolonyl, benzoxazinyl, benzoxazinonyl, benzoxazolonyl, benzothienyl, benzothiophenyl, benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furopyrrolo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl).

[0139] ​The term "heterocycloalkyl" refers to a saturated ring having carbon atoms and at least one heteroatom. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkyl groups can include single and multiple rings, such as 3- to 10-membered single rings, 6- to 12-membered bicyclic rings, 5- to 12-membered spirobicyclic rings, and 5- to 12-membered bridged rings. The heteroatoms in the heterocycloalkyl group are optionally oxidized. If one or more nitrogen atoms are present, they are optionally quaternized. The heterocycloalkyl group is attached to the rest of the molecule through any atom of the heterocycloalkyl group, such as any carbon or nitrogen atom of the heterocycloalkyl group, as valency permits. Examples of heterocycloalkyl groups include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and 1,1-dioxo-thiomorpholinyl.

[0140] The term "heterocycloalkenyl" refers to an unsaturated ring having carbon atoms and at least one heteroatom, and at least one double bond between two ring carbons. Heterocycloalkenyl does not include heteroaryl rings. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Heterocycloalkenyl groups can include single and multiple rings, such as 3- to 10-membered single rings, 6- to 12-membered bicyclic rings, and 5- to 12-membered bridged rings. In other embodiments, the heterocycloalkenyl contains 5 to 7 carbon atoms. The heterocycloalkenyl group is attached to the rest of the molecule through a single bond. Examples of monocyclic cycloalkenyl groups include, for example, pyrroline (dihydropyrrole), pyrazoline (dihydropyrazole), imidazoline (dihydroimidazole), triazoline (dihydrotriazole), dihydrofuran, dihydrothiophene, oxazoline (dihydrooxazole), isoxazoline (dihydroisoxazole), thiazoline (dihydrothiazole), isothiazoline (dihydroisothiazole), oxadiazoline (dihydrooxadiazole), thiadiazoline (dihydrothiadiazole), dihydropyridine, tetrahydropyridine, dihydropyridazine, tetrahydropyridazine, dihydropyrimidine, tetrahydropyrimidine, dihydropyrazine, tetrahydropyrazine, pyran, dihydropyran, thiopyran, dihydrothiopyran, dioxin, dihydrodioxin, oxazine, dihydrooxazine, thiazine, and dihydrothiazine.

[0141] The term "substituted" refers to moieties having a substituent replacing a hydrogen on one or more carbons or substitutable heteroatoms (e.g., NH or NH2) of the compound. It should be understood that "substitution" or "substituted with" includes the implicit proviso that the substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e. a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substitution refers to moieties in which two hydrogen atoms on the same carbon atom are replaced with a substituent, for example, two hydrogen atoms on a single carbon are replaced with oxo, imino, or thioxo groups. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for

[0142] In some embodiments, substituents can include any of the substituents described herein, for example: halogen, hydroxyl, oxo (=0), thioxo (=S), cyano (-CN), nitro (-N02), imino (=N-H), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wheret is 1 or 2), -R b -S(O)t R a (wheret is 1 or 2), -R b -S(O) t OR a (wheret is 1 or 2) and -R b -S(O) t N(R a )2(wheret is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl, any of which can be optionally substituted by alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo(=0), thioxo(=S), cyano(-CN), nitro(-N02), imino(=N-H), hydroxyimino(=N-OH), hydrazine(=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wheret is 1 or 2), -R b -S(O) t R a (wheret is 1 or 2), -R b -S(O) t OR a (wheret is 1 or 2) and -R b -S(O) t N(Ra )2(wherein t is 1 or 2) substituents; wherein each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R a may be optionally substituted with valence permitting, alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo(=0), thioxo(=S), cyano(-CN), nitro(-N02), imine(=N-H), oxime(=N-OH), hydrazine(=N-NH2), -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2), and -R b -S(O) t N(R a )2(wherein t is 1 or 2); and wherein each R b is independently selected from a direct bond, or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R cis a straight-chain or branched alkylene, alkenylene, or alkynylene chain.

[0143] A double bond to an oxygen atom, e.g., an oxo group, is represented herein as “=0” and “(0)”. A double bond to a nitrogen atom is represented as “=NR” and “(NR)”. A double bond to a sulfur atom is represented as “=S” and “(S)”.

[0144] As used herein, the phrases “parenteral administration” and “parenterally administered” mean modes of administration other than oral or topical administration, usually by injection, including without limitation intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, infracapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0145] The phrase “pharmaceutically acceptable” is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0146] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laureate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0147] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. In some embodiments, the pharmaceutically acceptable base addition salt is selected from the group consisting of an ammonium salt, a potassium salt, a sodium salt, a calcium salt, and a magnesium salt.

[0148] As used herein, "treatment" or "treating" refers to a method for obtaining beneficial or desired results, including but not limited to therapeutic benefit and / or prophylactic benefit, with respect to a disease, disorder, or medical condition. Therapeutic benefit can include, for example, eradication or amelioration of the underlying disease being treated. Additionally, therapeutic benefit can include, for example, eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that the subject no longer suffers from the disorder, although the subject can still be afflicted with the disorder. In certain embodiments, for prophylactic benefit, the composition is administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not yet been made. Treatment by administration of the compounds described herein does not require the involvement of a medical professional.

[0149] Compounds

[0150] The following is a discussion of compounds and salts thereof that can be used in the methods of the present disclosure. The compounds and salts are described in Formula (I), (la), (lb), (lc), (Id), (le), (II), (Ila), and (III).

[0151] In certain aspects, disclosed herein is a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:

[0152]

[0153] or a salt thereof, wherein:

[0154] each X is independently selected from C(R 3 ), N, and N +(-O - ), wherein at least one X is N or N + (-O - );

[0155] A is selected from -O- and -NR 4 -、-CR 5 R 6 -、-C(O)-、-S-、-S(O)- and -S(O)2-;

[0156] R 1 Selected from:

[0157] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 The carbon ring and 3 to 10-membered heterocycles are substituted with substituents, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0158] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents on the carbocyclic ring and 3 to 10-membered heterocycles; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; or

[0159] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced

[0160] When A is -NR 4 - At that time, R 1 Additionally, it is selected from hydrogen, and when A is -C(O)-, R 1 Additionally selected from -N(R) 10 )2 and -OR 10 ;

[0161] Each R 2 Selected independently

[0162] Halogen, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R10 -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, and -CN;

[0163] C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =0, =S, =N(R 10 ), and -CN; and

[0164] C 3-10 carbocyclyl, optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10)2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ),–CN、C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles; of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced;

[0165] R 3 R 5 and R 6 Each is selected independently from:

[0166] Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0167] R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 5 With R 1 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced;

[0168] R 4 Selected independently from:

[0169] Hydrogen; and

[0170] C 1-6alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; or

[0171] R 4 and R 1 together form a 3- to 10-membered heterocyclic ring, optionally substituted with one or more R 9 ;

[0172] R 7 and R 8 are each independently selected from the group consisting of:

[0173] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and C 10 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 , -SR 10 , -N(R 2-6 )2, -NO2, and -CN;

[0174] each R 9 is independently selected from the group consisting of:

[0175] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and

[0176] C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 Substituents of -CN and -CN are substituted;

[0177] Each R 10 Selected independently from:

[0178] hydrogen;

[0179] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC. 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and

[0180] C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-6 Substituents of (halogenated alkyl) groups;

[0181] n is 0, 1, or 2;

[0182] p is 0, 1, or 2; and

[0183] q is 1, 2, 3, 4, or 5, and when R 1 is other than -CH3, q is further selected from 0.

[0184] In certain aspects, for a compound or salt of Formula (I):

[0185] R 1 is selected from:

[0186] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 carbon ring, and 3- to 10-membered heterocycle, wherein the C 3-10 carbon ring and 3- to 10-membered heterocycle are each optionally substituted with one or more R 9 ; and

[0187] C 3-10 carbon ring and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10)2, -OC(O)N(R 10 )2, -N(R 10 )2, -C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =0, =S, =N(R 10 ), and -CN; or

[0188] R 1 and R 3 together form a 5- to 10-membered heterocyclic ring or a C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring is optionally substituted with one or more R 9 ; or R 1 and R 5 together form a 3- to 10-membered heterocyclic ring or a saturated C 3-10 carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3-10 carbocyclic ring is optionally substituted with one or more R 9 ; or R 1 and R 4 together form a 3- to 10-membered heterocyclic ring, wherein the 3- to 10-membered heterocyclic ring is optionally substituted with one or more R 9 ; and

[0189] when A is -NR 4 -, R 1 is additionally selected from the group consisting of hydrogen, and when A is -C(O)-, R 1 is additionally selected from the group consisting of -N(R 10 )2, and -OR 10 ;

[0190] each R 2 is independently selected from the group consisting of:

[0191] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 -NO2, and -CN;

[0192] C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and

[0193] C 3-10 carbocyclyl, optionally substituted with one or more substituents independently selected from halo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN;

[0194] each R is independently selected from the group consisting of: 10 is independently selected from the group consisting of:

[0195] hydrogen;

[0196] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle, and 3- to 10-membered heterocycle; and

[0197] C 3-10 carbocycle, and 3- to 10-membered heterocycle, wherein each is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and haloalkyl.

[0198] In certain embodiments, for a compound or salt of Formula (I), each X is independently selected from C(R 3 ) and N, wherein at least one X is N. In some embodiments, one X is N and one X is C(R 3 ). In some embodiments, one X is N + (-O - ) and one X is C(R 3 ). In some embodiments, each X is N. In some embodiments, one X is N, and one X is N + (-O - ).

[0199] In certain embodiments, for a compound or salt of Formula (I), each X is further selected from C(R 3 ).

[0200] In some embodiments, a compound of Formula (I) or salt thereof is represented by Formula (la):

[0201] In certain embodiments, for a compound or salt of Formula (I), each R is independently selected from the group consisting of:

[0202] In some embodiments, the compound of Formula (I), or salt thereof, is represented by Formula (Ib):

[0203]

[0204] In some embodiments, the compound of Formula (I), or salt thereof, is represented by Formula (Ic):

[0205]

[0206] In some embodiments, the compound of Formula (I), or salt thereof, is represented by Formula (Id):

[0207]

[0208] In some embodiments, the compound of Formula (I), or salt thereof, is represented by Formula (Ia) or (Ib):

[0209]

[0210] In some embodiments, the compound of Formula (I), or salt thereof, is represented by Formula (Ic) or (Id):

[0211]

[0212] In some embodiments, the compound of Formula (I), or salt thereof, is represented by Formula (Ia) or (Ic):

[0213]

[0214] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), A is selected from -0-, -NR 4 -, -CR 5 R 6 -, and -C(O)-. In some embodiments, A is selected from -0- and -NR 4 . In some embodiments, A is -0-. In some embodiments, A is -C(O)-. In some embodiments, A is -NR 4 -, such as -NH-.

[0215] In certain embodiments, for a compound or salt of any one of Formula (I), (Ia), (Ib), (Ic), or (Id), R 1 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 .)2, -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 10 , -C(O)OR 10 , -OC(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 arbon and 3- to 10-membered heterocycle, wherein the C 3-10 arbon and 3- to 10-membered heterocycle are each optionally substituted with one or more R 9 . In some embodiments, R 1 is C 1-6 alkyl substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10

[0216] , -C(O)OR 10 , -OC(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 arbon and 3- to 10-membered heterocycle, wherein the C 3-10 arbon and 3- to 10-membered heterocycle are each optionally substituted with one or more R 9 . In some embodiments, R 1 is C 1-6 alkyl substituted with one or more substituents independently selected from halogen, -OR 10 , -N(R​10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -NO2, =O, =N(R 10 ), -CN, C 3-10 carbon and 3- to 10-membered heterocycle, wherein the C 3-10 carbon and 3- to 10-membered heterocycle are each optionally substituted with one or more R 9 . In some embodiments, R 1 is selected from C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 carbon and 3- to 10-membered heterocycle, wherein the C 3-10 carbon and 3- to 10-membered heterocycle are each optionally substituted with one or more R 9 . In some embodiments, R 1 is C 1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR 10 , -N(R 10 )2, -NO2, =O, -CN, C 3-10 carbon and 3- to 10-membered heterocycle, wherein the C 3-10 carbon and 3- to 10-membered heterocycle are each optionally substituted with one or more R 9 . In some embodiments, R 1 is C 1-3 alkyl substituted with one or more halogen substituents. In some embodiments, R 1 is C 1-3 fluoroalkyl. In some embodiments, R 1 is selected from -CHF2, -CH2F, -CF3, -CH2CHF2, CH2CH2F or -CH2CF3. In some embodiments, R 1 is CH2CN. In some embodiments, R 1 is not unsubstituted methyl. In some embodiments, R 1 is -NH2. In some embodiments, R 1 is -NH2 when A is -C(O)-. In some embodiments, R 1for -OR 10 substituted C 1-3 alkyl, wherein R 10 is C 1-3 alkyl substituted with one or more halogen. In some embodiments, R 1 is -CH2CH2-OR 10 , wherein R 10 is -CHF2or -CH3. In some embodiments, R 1 is C 1-3 alkyl substituted with =0. In some embodiments, R 1 is -C(O)-CH3. In some embodiments, R 1 is -CH3. In some embodiments, R 1 is selected from C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 9 . In some embodiments, R 1 is C 3-10 carbocycle. In some embodiments, R 1 is C 3-5 carbocycle. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is C 1-3 alkyl substituted with a 4- to 6-membered heterocycle, wherein the 4- to 6-membered heterocycle is substituted with one or more R 9 . In some embodiments, R 1 is methyl substituted with a 4- to 6-membered heterocycle selected from:

[0217] In certain embodiments, for a compound or salt of Formula (I), (la), (lb), (Ic), or (Id), R 1 is selected from C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , and a 3- to 6-membered heterocycle optionally substituted with one or more R 9 . In some embodiments, R 9 is C 3-5 carbocycle optionally substituted with one or more R

[0218] In certain embodiments, for a compound or salt of Formula (I), (la), (lb), (Ic), or (Id), R 1 is selected from C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10and optionally substituted by one or more R 9 substituted 3- to 6-membered heterocycle and optionally substituted by one or more R 9 substituted C 3-5 carbon ring, wherein each R 9 is selected from C 1-3 alkyl, C 1-3 haloalkyl, and halogen.

[0219] In certain embodiments, for a compound or salt of Formula (I), (la), (lb), (Ic), or (Id), R 1 is selected from -CH3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -C(=0)CH3,

[0220] In certain embodiments, for a compound or salt of any one of Formula (I), (la), (lb), (Ic), or (Id), R 1 is selected from optionally substituted C3-C6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl, and spiro pentyl, any of which can be optionally substituted. In certain embodiments, R 1 is selected from alkyl, for example, methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any of which can be optionally substituted. In certain embodiments, R 1 is selected from: In certain embodiments, R 1 is selected from: In certain embodiments, R 1 is selected from optionally substituted In some embodiments, for a compound or salt of any one of Formula (I), (la), (lb), (Ic), or (Id), R 1 is selected from optionally substituted C3cycloalkyl.

[0221] In certain embodiments, for a compound or salt of Formula (I), R 1 together with R 3 form a 5- to 10-membered heterocycle or C 5-10 carbon ring, wherein the 5- to 10-membered heterocycle or C 5-10 carbon ring is optionally substituted by one or more R 9 In some embodiments, R 1 together with R 3 form a C 5-10 carbon ring or 5- to 10-membered heterocycle, such as C 5-6 carbon ring or 5- to 6-membered heterocycle, for example:

[0222]

[0223]

[0224] In some embodiments, for compounds or salts of formula (I), R 1 With R 5 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced. In some implementations, R 1 With R 5 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbon rings, for example:

[0225]

[0226] In some embodiments, for compounds or salts of formula (I), R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced. In some implementations, R 1 With R 4 Together they form 3- to 10-membered heterocycles, for example:

[0227]

[0228] In some implementations, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), or (Id), R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 What it replaced.

[0229] In some embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), or (Id), R 1 With R 4 The 3- to 10-membered heterocycles formed together are selected from 4-, 5-, 6-, or 7-membered rings, any one of which is optionally bounded by one or more R... 9 What it replaced.

[0230] In some embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), or (Id), R 1 With R 4 The 3- to 10-membered heterocycles formed together are selected from: Any one of them may be arbitrarily assigned to one or more R9 substituted.

[0231] In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), or (Id), each R 1 together with R 4 forms a 3- to 10-membered heterocycle selected from:

[0232] In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), or (Id), when R 2 is present at one or both ortho positions of the phenyl ring relative to the point of attachment to the remainder of the molecule, each ortho R 2 is independently selected from the group consisting of halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and C 1-3 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN. In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), or (Id), when R 2 is present at one or both ortho positions of the phenyl ring relative to the point of attachment to the remainder of the molecule, each R 2 is independently selected from the group consisting of halogen, -OH, -OCH3, -OCF3, and C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen.

[0233] In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), or (Id), if R 2 is present at one or both ortho positions of the phenyl ring relative to the point of attachment to the remainder of the molecule, R 2 is not selected from a carbocycle or heterocycle. In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), or (Id), R 2 is not present at one or both ortho positions of the phenyl ring relative to the point of attachment to the remainder of the molecule.

[0234] In some embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), or (Id), each R 2 is independently selected from the group consisting of halogen, -OR 10 , -SR 10, -N(R 10 )2, -NO2, -CN, and C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN. In some embodiments, for a compound or salt according to any one of formulae (I), (la), (lb), (Ic), or (Id), each R 2 is selected from -Cl, -F, and -OH.

[0235] In certain embodiments, for a compound or salt according to any one of formulae (I), (la), (lb), (Ic), or (Id), R 2 is selected from C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl, and spiro pentyl, any of which is optionally substituted. In certain embodiments, R 2 is

[0236]

[0237] In certain embodiments, for a compound or salt according to any one of formulae (I), (la), (lb), (Ic), or (Id), q is 0, 1, or 2. In certain embodiments, q is 0.

[0238] In certain embodiments, for a compound or salt according to any one of formulae (I), (la), (lb), (Ic), or (Id), each R 3 is selected from hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2

[0239] , -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is taken together with R 1 to form a 5- to 6-membered heterocycle or C 5-6 carbocycle, wherein the 5- to 6-membered heterocycle or C 5-6 carbocycle is optionally substituted with one or more R 9 . In some embodiments, R 3 is taken together with R 1together form a 5-membered heterocycle substituted with zero, one, or two methyl groups, for example:

[0240]

[0241] In certain embodiments, for a compound or salt according to any one of Formulae (I), (la), (lb), (Ic), (Id), R 4 is independently selected from hydrogen; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; or R 4 together with R 1 form a 3- to 10-membered heterocycle optionally substituted with one or more R 9 . In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is methyl. In some embodiments, R 4 together with R 1 form a 4- to 5-membered heterocycle optionally substituted with one or more R 9 , wherein R 9 is selected from methyl, -CH2F, -CHF2, -CF3, -F, -OCF3, and -OCHF2.

[0242] In certain embodiments, for a compound or salt according to any one of Formulae (I), (la), (lb), (Ic), (Id), each R 5 and R 6 is independently selected from hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN. In some embodiments, R 1 together with R 5 form a 3- to 10-membered heterocycle or a saturated C 3-10 carbocycle. In some embodiments, R 1 together with R 5 form a cyclopropyl ring.

[0243] In certain embodiments, for a compound or salt according to any one of Formulae (I), (la), (lb), (Ic), (Id), each R7 and R 8 is independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and C 10 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 2-6 )2, -NO2, and -CN.

[0244] In certain embodiments, for a compound or salt of any one of Formulas (I), (Ia), (Ib), (Ic), or (Id), each R 9 is independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =O, =S, -CN; and C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2

[0245] , and -CN. In some embodiments, R 9 is halogen. In some embodiments, R 9 is -F. In some embodiments, R 9 is C 1-3 haloalkyl. In some embodiments, R 9 is C 1-3 alkyl substituted with one or more fluoro substituents. In some embodiments, R 9 is -CH2F, -CHF2, or -CF3. In some embodiments, R 9 is unsubstituted C 1-3 alkyl. In some embodiments, R 9 is methyl. In some embodiments, R 9 is -OR 10 . In some embodiments, R 9 is -OR 10 , and R 10 is C 1-3 haloalkyl. In some embodiments, R 9 is -OR 10 , and R 10 is -CH2F, -CHF2, or -CF3.It can be -CH2F, -CHF2, or -CF3. In some implementations, the two R... 9 The groups together form, optionally by one or more R 10 Replaced 3 to 10-membered heterocyclic rings or C 3-10 Carbon rings. In some implementations, two R... 9 The groups together form a spirocyclic C12 substituents that are substituted with one or more fluorine substituents. 3-5 Carbon rings. In some implementations, two R... 9 The groups together form a spirocyclic cyclobutane substituted with two fluorine substituents.

[0246] In some embodiments, for a compound or salt of any one of formulas (I), (Ia), (Ib), (Ic), or (Id), each R 10 Independently selected from hydrogen; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents on carbocyclic rings, 3- to 10-membered heterocycles; and C 3-10 A carbon ring and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 1-6 Alkyl, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups. In some embodiments, R... 10 It is -F.

[0247] In some implementations, n is 0 for any compound or salt of formula (I), (Ia), (Ib), (Ic), (Id).

[0248] In some implementations, p is 0 for any compound or salt of formula (I), (Ia), (Ib), (Ic), (Id).

[0249] In some embodiments, compounds of formula (I) are represented by formula (Ie):

[0250]

[0251] or a salt thereof, wherein:

[0252] A is selected from -0-, -NR 4 -, -CR 5 R 6 and -C(O)-;

[0253] X is independently selected from C(R 3 ) and N;

[0254] R 1 is selected from:

[0255] C 1-6 alkyl optionally substituted with one or more substituents independently selected from halo, -OR

[0256] OR 10 , -N(R 10 )2, -C(O)R 10 , -CN, C 3-6 carbocycle and 4- to 6-membered heterocycle, wherein said C 3-6 carbocycle and 4- to 6-membered heterocycle are each optionally substituted with one or more R 9 ; and

[0257] C 3-6 carbocycle; or

[0258] R 1 and R 3 together form a 5- to 10-membered heterocycle, wherein said 5- to 10-membered heterocycle is optionally substituted with one or more R 9 ; or R 1 and R 5 together form a saturated C 3-5 carbocycle; or R 1 and R 4 together form a 4- to 6-membered heterocycle, wherein said 4

[0259] to 6-membered heterocycle is optionally substituted with one or more R 9 ; and when A is -C(O)-, R 1 is additionally selected from -N(R 10 )2and -OR 10 ;

[0260] each R 2 is independently selected from halo and halo, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN;

[0261] each R 9 is independently selected from:

[0262] Halogen, -OR 10 -SR 10 -N(R) 10 )2, -NO2, -CN; and

[0263] C 1-3 Alkyl groups, optionally composed of one or more elements independently selected from halogens, -

[0264] OR 10 -SR 10 -N(R) 10 )2, -NO2 and -CN substituents are substituted; and the two R 9 The groups together form, optionally by one or more R 10 Replacement 4

[0265] Up to 6-membered heterocyclic or C 3-6 Carbocyclic rings, wherein the 4- to 6-membered heterocyclic rings or C 3-6 The carbon ring may be optionally a helical ring;

[0266] Each R 10 Selected independently

[0267] Hydrogen; and

[0268] C 1-6 Alkyl groups, optionally composed of one or more elements independently selected from halogens, -

[0269] CN, -OH, -SH, -NO2, -NH2, -OC 1-6 Alkyl, -N(C) 1-6 alkyl)2 and -NH(C 1-6 It is replaced by substituents of alkyl groups.

[0270] In some implementations, for compounds or salts of formula (Ie): each R 9 Selected independently from:

[0271] Halogen, -OR 10 -SR 10 -N(R) 10 )2, -NO2, -CN; and

[0272] C 1-3 Alkyl groups, optionally composed of one or more elements independently selected from halogens, -

[0273] OR 10 -SR 10 -N(R) 10 Substituents of -NO2 and -CN are present.

[0274] In certain embodiments, for a compound or salt of any one of Formulas (I), (la), (lb), (lc), or (Id), R 1 -A is further selected from hydrogen. For example, a compound of the disclosure can be represented as: or a salt thereof, wherein R 7 , R 2 , X, p, q, and n are as previously described for Formula (I). In certain embodiments, for a compound or salt of any one of Formulas (I), (la), (lb), (lc), or (Id), R 1 -A is further selected from halogen and C1-C3 alkyl, e.g., C2-C3 alkyl. In certain embodiments, for a compound or salt of any one of Formulas (I), (la), (lb), (lc), or (Id), R 1 -A is further selected from halogen.

[0275] In certain embodiments, a compound of the disclosure is selected from the compounds of Table 1, or a salt thereof.

[0276] In certain aspects, disclosed herein are compounds represented by Formula (II’):

[0277]

[0278] or a salt thereof, wherein:

[0279] T is selected from -O-, -NR 14 -, -CR 15 R 16 -, -C(O)-, -S-, -S(O)-, and -S(O)2;

[0280] R 11 is selected from;

[0281] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each is substituted with one or more groups independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -

[0282] C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -

[0283] OC(O)N(R 20 )2, -N(R20 )C(O)OR 20 -C(O)OR 20 -OC(O)R 20 -

[0284] S(O)R 20 -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), –CN, C 3-10 carbon

[0285] The ring and 3- to 10-membered heterocyclic substituents are substituted, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 19 Replaced;

[0286] And C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -OR 20 -SR 20 -

[0287] N(R 20 )2、-C(O)R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -

[0288] N(R 20 )C(O)N(R 20 )2、-OC(O)N(R 20 )2、-

[0289] N(R 20 )C(O)OR 20 -C(O)OR 20 -OC(O)R 20 -S(O)R 20 -

[0290] S(O)2R 20 , -NO2, =O, =S, =N(R 20 Substituents of -CN and -CN; or

[0291] R 11 With R 17 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 19 Replaced; or R 11 With R15 together form a 3- to 10-membered heterocycle or a saturated C 3-10 carbon ring, wherein the 3- to 10-membered heterocycle or saturated C 3-10 carbon ring is optionally substituted with one or more R 19 substituents;

[0292] or R 11 together form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more R 14 substituents; 19

[0293] when T is -NR 14 , R 11 is additionally selected from hydrogen, and when T is -C(O)-

[0294] , R 11 is additionally selected from -N(R 20 )2and -OR 20 ;

[0295] each R 12 is independently selected from:

[0296] halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2,

[0297] -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2,

[0298] N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 ,

[0299] -NO2, -CN;

[0300] C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, wherein each is optionally substituted with one or more independently selected halogen, -OR 20 , -SR 20 , ​

[0301] N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -

[0302] N(R 20 )C(O)R 20 , -C(O)OR 20 , -N(R 20 )C(O)N(R 20 )2, -

[0303] OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -

[0304] S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and -CN; and

[0305] C 3-10 carbon ring optionally substituted with one or more substituents independently selected from halogen, -

[0306] OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -

[0307] N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -

[0308] N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -

[0309] S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and -CN; R 14 is independently selected from:

[0310] hydrogen; and

[0311] C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR

[0312] OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN; or

[0313] R 14 and R 11 together form a 3- to 10-membered heterocyclic ring optionally substituted with one or more R 19 ;

[0314] R 15 and R 16 are independently selected from the group consisting of:

[0315] halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN;

[0316] or R 15 and R 11 together form a saturated C 3-10 carbocyclic or 3- to 10-membered hetero

[0317] cyclic ring optionally substituted with one or more R 19 ;

[0318] each R 17 and R 18 is independently selected from the group consisting of:

[0319] halogen, -SR 20 , -N(R 20 )2, -NO2, -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 20 , -SR 20 , -N(R 20 )2, -

[0320] NO2, and -CN; or

[0321] R 17 and R 11 together form a C 5-10carbocycle or 5- to 10-membered heterocycle, each of which is optionally substituted with one or more R 19 ;

[0322] R 19 is independently selected from:

[0323] halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2,

[0324] -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2,

[0325] N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 ,

[0326] S(O)2R 20 , -NO2, =O, =S, =N(R 10 ), and -CN; and

[0327] C 1-3 alkyl, C 2-3 alkenyl, and C 2-3 alkynyl, each of which is optionally substituted with one or more R 20 ; 20

[0328] N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 ,

[0329] N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2,

[0330] N(R 20 )C(O)OR 20 , -C(O)OR 20 , -OC(O)R​20 -S(O)R 20 -S(O)2R 20 ,

[0331] -NO2, =O, =S, =N(R) 20 Substituents of -CN and -CN are used;

[0332] Each R 20 Selected independently from:

[0333] hydrogen;

[0334] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogens, -CN, -OH, -SH, -NO2, -NH2, ...

[0335] =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and

[0336] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O,

[0337] =S、-OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 alkyl

[0338] (base), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0339] w is 0, 1, or 2

[0340] z is 0, 1, or 2; and v is 1, 2, 3, 4, or 5, and when R 11 If it is not -CH3, v is further selected from 0.

[0341] In some respects, this paper discloses compounds represented by formula (II):

[0342]

[0343] or salts thereof, wherein:

[0344] T is selected from -0-, -NR 14 -, -CR 15 R 16 -, -C(O)-, -S-, -S(O)-, and -S(0)2;

[0345] R 11 is selected from:

[0346] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each is substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(0)R 20 , -

[0347] C(0)N(R 20 )2, -N(R 20 )C(0)R 20 , -N(R 20 )C(0)N(R 20 )2, -

[0348] OC(0)N(R 20 )2, -N(R 20 )C(0)OR 20 , -C(0)OR 20 , -OC(0)R 20 , -

[0349] S(0)R 20 , -S(0)2R 20 , -N02, =0, =S, =N(R 20 ), -CN, C 3-5 carbon

[0350] ring, and 3- to 10-membered heterocycle, wherein each is optionally substituted with one or more R 3-5 substituents;

[0351] to 10-membered heterocycle is each optionally substituted with one or more R 19 substituents;

[0352] and C 3-10 carbon ring and 3- to 10-membered heterocycle, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -

[0353] N(R20 )2, -C(O)R 20 , 20 )2, -N(R 20 )C(O)R 20 ,

[0354] N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2,

[0355] N(R 20 )C(O)OR 20 , 20 -C(O)OR 20 , 20 -OC(O)R 20 , 20 -S(O)R 11 ,

[0356] S(O)2R 15 , 3-10 -NO2, =O, =S, =N(R 3-10 ) and -CN; or

[0357] R 19 and R 11 together form a 3- to 10-membered heterocyclic or saturated C 14 carbocyclic ring, wherein said 3- to 10-membered heterocyclic or saturated C 19 carbocyclic ring is optionally substituted with one or more R 14 ; or R 11 and R 11 together form a 3- to 10-membered heterocyclic ring, wherein said 3- to 10-membered heterocyclic ring is optionally substituted with one or more R

[0358] ; when T is -NR 20 -, R 20 is additionally selected from the group consisting of hydrogen, and when T is -C(O)-

[0359] , R 12 is additionally selected from the group consisting of -N(R 20 )2and -OR 20 ;

[0360] each R 20 is independently selected from the group consisting of:

[0361] halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2,

[0363] -N(R 20 )2, -C(O)N(R 20 )2, -OC(O)N(R 20 )2, -C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, -CN;

[0364] C 1-3 alkyl optionally substituted with one or more substituents independently selected from halo, -

[0365] OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -

[0366] N(R 20 )C(O)R 20 , -C(O)OR 20 , -N(R 20 )C(O)N(R 20 )2, -

[0367] OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -OC(O)R 20 , -S(O)R 20 , -

[0368] S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), and -CN; and

[0369] C 3-10 carbocyclyl optionally substituted with one or more substituents independently selected from halo, -

[0370] OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -

[0371] N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R20 )2、-

[0372] N(R 20 )C(O)OR 20 -C(O)OR 20 -OC(O)R 20 -S(O)R 20 -

[0373] S(O)2R 20 , -NO2, =O, =S, =N(R 20 Substituents of ) and -CN; R 14 Selected independently

[0374] Hydrogen; and

[0375] C 1-6 Alkyl groups, optionally composed of one or more elements independently selected from halogens, -

[0376] OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN; or

[0377] R 14 With R 11 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 19 Replaced;

[0378] R 15 With R 11 Together they form saturated C 3-10 A carbon ring or a 3- to 10-membered heterocycle, optionally separated by one or more R... 19 Replaced;

[0379] R 16 Selected independently from:

[0380] Hydrogen, halogen, -OR 20 -SR 20 -N(R) 20 2, -NO2, -CN and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN;

[0381] R 18 Selected independently from:

[0382] Halogen, -SR 20 -N(R) 202. -NO2 and optionally one or more independently selected from halogens, -OR 20 -SR 20 -N(R) 20 2. C replaced by substituents of -NO2 and -CN 2-6 alkyl;

[0383] R 19 Selected independently

[0384] Halogen, -OR 20 -SR 20 -N(R) 20 )2、-C(O)R 20 -C(O)N(R) 20 2.

[0385] -N(R 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-OC(O)N(R 20 )2、-

[0386] N(R 20 )C(O)OR 20 -C(O)OR 20 -OC(O)R 20 -S(O)R 20 -

[0387] S(O)2R 20 , -NO2, =O, =S, =N(R 10 ) and -CN; and

[0388] C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 20 -SR 20 -

[0389] N(R 20 )2、-C(O)R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -

[0390] N(R 20 )C(O)N(R 20 )2、-OC(O)N(R 20 )2、-

[0391] N(R 20 )C(O)OR 20 ,-C(O)OR 20 -OC(O)R 20 -S(O)R 20 -S(O)2R 20 ,

[0392] -NO2, =O, =S, =N(R) 20 Substituents of -CN and -CN are used;

[0393] Each R 20 Selected independently

[0394] hydrogen;

[0395] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more groups selected from halogens, -CN, -OH, -SH, -NO2, -NH2, ...

[0396] =O, =S, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), C 3-10 Substituents in the carbocyclic ring and 3- to 10-membered heterocycles; and

[0397] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -CN, -OH, -SH, -NO2, -NH2, =O,

[0398] =S、-OC 1-6 Alkyl, -SC 1-6 Alkyl, -N(C) 1-6 alkyl)2、-NH(C 1-6 alkyl

[0399] (base), C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Substituents include carbocyclic rings, 3- to 10-membered heterocycles, and haloalkyl groups;

[0400] z is 0, 1, or 2; and v is 1, 2, 3, 4, or 5.

[0401] In some embodiments, for compounds or salts of formula (II) or (II'), T is selected from -O-, -NR. 14 -、-CR 15R 16 - and -C(O)-. In some embodiments, T is selected from -O- and -NR 14 . In some embodiments, T is -O-. In some embodiments, T is -C(O)-. In some embodiments, T is -NR 14 - such as -NH-.

[0402] In certain embodiments, for a compound or salt of any one of Formula (II) or (II'), R 11 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20

[0403] , -C(O)OR 20 , -OC(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -CN, C 3-5 aromatic and 3- to 10-membered heterocycle, wherein the C 3-5 aromatic and 3- to 10-membered heterocycle are each optionally substituted with one or more R 19 . In some embodiments, R 11 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -OC(O)N(R20 )2, -N(R 20 )C(O)OR 20 , -S(O)R 20 , -S(O)2R 20 , -NO2, =O, =S, =N(R 20 ), -CN, C 3-5 aromatic, and 3- to 10-membered heterocycle, wherein the C 3-5 aromatic and 3- to 10-membered heterocycle are each optionally substituted with one or more R 19 . In some embodiments, R 11 is C 1-6 alkyl substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -NO2, =O, =N(R 20 ), -CN, C 3-5 aromatic, and 3- to 10-membered heterocycle, wherein the C 3-5 aromatic and 3- to 10-membered heterocycle are each optionally substituted with one or more R 19 . In some embodiments, R 11 is selected from C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, =O, =S, =N(R 20 ), -CN, C 3-5 aromatic, and 3- to 10-membered heterocycle, wherein the C 3-5 aromatic and 3- to 10-membered heterocycle are each optionally substituted with one or more R 19 . In some embodiments, R 11 is C 1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR 20 , -N(R 20 )2, -NO2, =O, -CN, C 3-5 aromatic, and 3- to 10-membered heterocycle, wherein the C 3-5 aromatic and 3- to 10-membered heterocycle are each optionally substituted with one or more R 19 . In some embodiments, R 11C1-C6alkyl substituted with one or more halogen substituents. In some embodiments, R 1-3 alkyl. In some embodiments, R 11 is C 1-3 fluoroalkyl. In some embodiments, R 11 is selected from -CHF2, -CH2F, -CF3, -CH2CHF2, CH2CH2F, or -CH2CF3. In some embodiments, R 11 is CH2CN. In some embodiments, R 11 is not unsubstituted methyl. In some embodiments, R 11 is -NH2. In some embodiments, when A is -C(O)-, R 11 is -NH2. In some embodiments, R 11 is C 20 alkyl substituted with -OR 1-3 , wherein R 20 is C 1-3 alkyl substituted with one or more halogen substituents. In some embodiments, R 11 is -CH2CH2-OR 20 , wherein R 20 is -CHF2or -CH3. In some embodiments, R 11 is C 1-3 alkyl substituted with =O. In some embodiments, R 11 is -C(O)-CH3. In some embodiments, R 11 is -CH3. In some embodiments, R 11 is selected from C 3-5 carbocyclic and 3- to 10-membered heterocyclyl, wherein the C 3-5 carbocyclic and 3- to 10-membered heterocyclyl are each optionally substituted with one or more R 19 . In some embodiments, R 11 is C 3-5 carbocyclic. In some embodiments, R 11 is cyclopropyl. In some embodiments, R 11 is C 1-3 alkyl substituted with a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is substituted with one or more R 19 . In some embodiments, R 11 is methyl substituted with a 4- to 6-membered heterocyclyl selected from .

[0404] In certain embodiments, for a compound or salt of any one of Formula (II) or (II’), R 11selected from optionally substituted C3-C6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, bicyclopentyl, and spiro pentyl, any of which is optionally substituted. In certain embodiments, R 11 selected from alkyl, for example, methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, sec-butyl, any of which can be optionally substituted. In certain embodiments, R 11 selected from: In certain embodiments, R 11 selected from: In certain embodiments, R 11 selected from optionally substituted

[0405] In certain embodiments, for a compound or salt of Formula (II) or (II’), R 11 together with R 17 form a 5- to 10-membered heterocycle or C 5-10 carbocycle, wherein the 5- to 10-membered heterocycle or C 5-10 carbocycle is optionally substituted with one or more R 19 In some embodiments, R 11 together with R 17 form a C 5-10 carbocycle or 5- to 6-membered heterocycle, for example: 5-6 carbocycle or 5- to 6-membered heterocycle, for example:

[0406]

[0407] In certain embodiments, for a compound or salt of Formula (II) or (II’), R 11 together with R 15 form a 3- to 10-membered heterocycle or saturated C 3-10 carbocycle, wherein the 3- to 10-membered heterocycle or saturated C 3-10 carbocycle is optionally substituted with one or more R 19 In some embodiments, R 11 together with R 15 form a 3- to 10-membered heterocycle or saturated C 3-10 carbocycle, for example:

[0408]

[0409] In certain embodiments, for a compound or salt of Formula (II) or (II’), R 11 together with R 14 form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more R 19 In some embodiments, R 11 together with R14 Together they form 3- to 10-membered heterocycles, for example:

[0410]

[0411]

[0412] In some implementations, for any compound or salt of formula (II) or (II'), each R 12 Independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, -NO2, -CN and optionally selected independently by one or more halogens, -OR 20 -SR 20 -N(R) 20 2. C replaced by substituents of -NO2 and -CN 1-3 Alkyl group. In some embodiments, each R 12 Selected from -Cl, -F and -OH.

[0413] In some embodiments, for compounds or salts of formula (II) or (II'), R 12 Selected from C 3-6 Cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, dicyclopentyl, and spiropentyl, are optionally substituted. In some embodiments, R 12 for

[0414] In some implementations, v is 0, 1, or 2. In some implementations, v is 0.

[0415] In some embodiments, for compounds or salts of any of formula (II) or (II'), when R is present at one or two adjacent positions of the phenyl ring relative to the connection point with the rest of the molecule... 12 At that time, each neighboring R 12 Independently selected from halogens, -OR 20 -SR 20 -N(R) 20 2, -NO2, -CN and C 1-3 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, -NO2 and -CN substituents are substituted. In some embodiments, for compounds or salts of any of formula (II) or (II'), when R is present at one or two ortho positions of the phenyl ring relative to the connection point with the rest of the molecule. 12 At that time, each R 12Independently selected from halogens, –OH, -OCH3, -OCF3, and C 1-3 Alkyl groups, which are optionally substituted with one or more substituents independently selected from halogens.

[0416] In some embodiments, for a compound or salt of either formula (II) or (II'), if R is present at one or both adjacent positions of the phenyl ring relative to the connection point with the rest of the molecule... 12 Then R 12 Not selected from carbocyclic or heterocyclic rings. In some embodiments, for compounds or salts of any of formula (II) or (II'), R is absent at one or two adjacent positions of the phenyl ring relative to the junction with the remainder of the molecule. 12 .

[0417] In some embodiments, for compounds or salts of any one of formula (II) or (II'), R 14 Selected from hydrogen; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 20 -SR 20 -N(R) 20 )2, replaced by substituents of -NO2 and -CN; or R 14 With R 11 Together they form 3- to 10-membered heterocycles, which are optionally separated by one or more R... 19 Replaced. In some implementations, R 14 It is hydrogen. In some implementations, R 14 It is methyl. In some embodiments, R 14 With R 11 Together they form a 4- to 5-membered heterocycle, which is optionally separated by one or more R... 19 Replaced, of which R 19 Selected from methyl, -CH2F, -CHF2, -CF3, -F, -OCF3 and -OCHF2.

[0418] In some embodiments, for a compound or salt of either formula (II) or (II'), each R 15 and R 16 Independently selected from hydrogen, halogen, -OR 20 -SR 20 -N(R) 20 )2、-NO2

[0419] -CN and optionally one or more independently selected from halogens, -OR 20 -SR 20 -N(R) 20 2. C replaced by substituents of -NO2 and -CN 1-6alkyl. In some embodiments, R 11 together with R 15 form a 3- to 10-membered heterocycle or a saturated C 3-10 carbocycle. In some embodiments, R 11 together with R 15 form a cyclopropyl ring.

[0420] In certain embodiments, for a compound or salt of either of Formula (II) or (II’), each R 17 is independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and C 2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN.

[0421] In certain embodiments, for a compound or salt of either of Formula (II) or (II’), each R 18 is independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CHF2, -CF3, -CH2F, and C 2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN.

[0422] In some embodiments, for a compound or salt of either of Formula (II) or (II’), R 17 together with R 11 form a 5- to 6-membered heterocycle or a C 5-6 carbocycle, wherein the 5- to 6-membered heterocycle or C 5-6 carbocycle is optionally substituted with one or more R 19 . In some embodiments, R 17 together with R 11 form a 5-membered heterocycle substituted with zero, one, or two methyl groups, for example:

[0423]

[0424] In certain embodiments, for a compound or salt of either of Formula (II) or (II’), each R 19independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, =O, =S, -CN; and C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN. In some embodiments, R 19 is halogen. In some embodiments, R 19 is -F. In some embodiments, R 19 is C 1-3 haloalkyl. In some embodiments, R 19 is C 1-3 alkyl substituted with one or more fluoro substituents. In some embodiments, R 19 is -CH2F, -CHF2, or -CF3. In some embodiments, R 19 is unsubstituted C 1-3 alkyl. In some embodiments, R 19 is methyl. In some embodiments, R 19 is -OR 20 . In some embodiments, R 19 is -OR 20 , and R 20 is haloalkyl. In some embodiments, R 19 is -OR 20 , and R 20 is -CH2F, -CHF2, or -CF3. In some embodiments, two R 19 groups together form a 3- to 10-membered heterocycle or C 3-10 carbocycle optionally substituted with one or more R 20 . In some embodiments, two R 19 groups together form a spirocyclic C 3-5 carbocycle optionally substituted with one or more fluoro substituents. In some embodiments, two R 19 groups together form a spirocyclic cyclobutane optionally substituted with two fluoro substituents.

[0425] In certain embodiments, for a compound or salt of any one of Formula (II) or (II’), each R 20 is independently selected from hydrogen; and C 1-6alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, -S-C 3-10 alkyl, -N(C 3-10 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 alkyl, -S-C 20 alkyl, -N(C 14 alkyl)2, -NH(C 15 alkyl), C 16 alkyl, -S-C 11 alkyl, -N(C 1-6 alkyl)2, -NH(C 20 alkyl), C 20 alkyl, -S-C 20 alkyl, -N(C 3-6 alkyl)2, -NH(C

[0426] In certain embodiments, for the compounds of Formula (II), w is 0.

[0427] In certain embodiments, for the compounds of Formula (II) or (II'), z is 0.

[0428] In certain embodiments, for the compounds of Formula (II) or (II'), v is 1 or 2.

[0429] In certain embodiments, the compounds of Formula (II) are represented by Formula (IIa):

[0430]

[0431] or salts thereof, wherein:

[0432] A is selected from -O-, -NR 14 -, -CR 15 R 16 -, and -C(O)-;

[0433] R 11 is selected from:

[0434] C 1-6 alkyl, optionally substituted with one or more groups independently selected from halogen, -

[0435] OR 20 , -N(R 20 )2, -C(O)R 20 , -CN, C 3-6 alkyl, -S-Csubstituted by one or more R 3-6 substituted by one or more R 9 ; and

[0436] C 3-6 carbon ring; or

[0437] R 11 and R 13 together form a 5- to 10-membered heterocycle, wherein said 5- to 10-membered heterocycle is optionally substituted by one or more R 19 ; or R 11 and R 15 together form a saturated C 3-5 carbon ring; or R 11 and R 14 together form a 4- to 6-membered heterocycle, wherein said 4- to 6-membered heterocycle is optionally substituted by one or more R 19 ; and when A is -C(O)-, R 11 is additionally selected from -N(R 20 )2and -OR 20 ;

[0438] each R 12 is independently selected from the group consisting of halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN;

[0439] R 17 and R 11 together form a 5- to 10-membered heterocycle optionally substituted by one or more R 19 each R 19 is independently selected from the group consisting of:

[0440] halogen, -OR 20 , -SR 20 , -N(R 20 )2, -NO2, -CN; and

[0441] C 1-3 alkyl optionally substituted by one or more substituents independently selected from the group consisting of halogen, -

[0442] OR 20 , -SR 20 , -N(R 20 )2, -NO2, and -CN; and two R 19 groups together form a 4- to 6-membered heterocycle or C 20 carbon ring optionally substituted by one or more R 3-6 ;3-6 carbocyclic is optionally spirocyclic;

[0443] each R 20 is independently selected from:

[0444] hydrogen; and

[0445] C 1-6 alkyl, optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -SH, -NO2, -NH2, -O-C

[0446] CN, -OH, -SH, -NO2, -NH2, -O-C 1-6 alkyl, -N(C 1-6 alkyl)2, and -NH(C 1-6 alkyl);

[0447] w is 0 or 1; and v is 1 or 2.

[0448] In certain embodiments, for a compound or salt of Formula (II’) or (IIa), w is 0.

[0449] In certain embodiments, for a compound or salt of any one of Formula (II), (II’), or (IIa), R 11 -T is further selected from hydrogen. For example, a compound of Formula (II’) can be further selected from: or a salt thereof, wherein R 17 , R 18 , R 12 , w, z, and v are as described for Formula (II’).

[0450] In certain embodiments, a compound of the disclosure is selected from the compounds of Table 2, or a salt thereof.

[0451] Chemical entities having a carbon-carbon double bond or a carbon-nitrogen double bond can exist in Z- or E- (or cis- or trans-) form. In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, compounds described herein are also intended to include all Z-, E-, and tautomeric forms.

[0452] “Tautomer” refers to a molecule in which a proton is mobile from one atom of the molecule to another atom of the same molecule. In certain embodiments, compounds presented herein exist as tautomers. Where tautomerism is possible, a chemical equilibrium of the tautomers will exist. The exact proportions of tautomers depend on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibria include:

[0453]

[0454] In some embodiments, the compounds disclosed herein are used in various isotopically-labeled forms, e.g., with 2 H, 3 H, 11 C, 13 C, and / or 14 C content. In one particular embodiment, the compounds are deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of action of a drug.

[0455] Unless otherwise stated, the compounds described herein are intended to include both vaulted and vaulted compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this disclosure.

[0456] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be labeled with isotopes such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). Isotopic substitution with 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 I are all contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0457] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are replaced by 2 H atoms are replaced by deuterium. Methods for the synthesis of deuterium-containing compounds are known in the art, including by way of non-limiting example, the following synthetic methods.

[0458] Deuterium-substituted compounds are synthesized using various methods, such as described in: Dean, Dennis C., ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George, W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0459] Deuterated starting materials are readily available and subjected to the synthetic methods described herein to provide synthesis of deuterium-containing compounds. A large number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0460] The compounds of the present application also include crystalline forms and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0461] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present disclosure that are sufficiently acidic, sufficiently basic, or both, can react with any of a number of inorganic bases, inorganic and organic acids, and other organic compounds to form a salt. Alternatively, a compound that is inherently charged, such as a compound bearing a quaternary nitrogen, can form a salt with a suitable counterion, such as a halide, e.g., bromide, chloride, or fluoride, particularly bromide.

[0462] In some instances, the compounds described herein can exist in diastereomeric, enantiomeric or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as appropriate mixtures thereof. Separation of stereoisomers can be achieved by chromatographic methods or by separation of mixtures of diastereomers or enantiomers by recrystallization or chromatography or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981, incorporated herein by reference). Stereoisomers can also be obtained by stereoselective synthesis.

[0463] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein can be in the form of a pharmaceutically acceptable salt. Likewise, in some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0464] In certain embodiments, a compound or salt of a compound can be a prodrug, e.g., where a hydroxyl group in the parent compound is present as an ester or carbonate, or a carboxylic acid present in the parent compound is present as an ester. The term "prodrug" is intended to encompass compounds which, under physiologic conditions, are converted to the drug of the present disclosure. One method for making a prodrug includes one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity in the host animal, e.g., by a particular target cell in the host animal. For example, esters or carbonates, e.g., of alcohols or carboxylic acids and esters of phosphates, are preferred prodrugs of the present disclosure.

[0465] Prodrug forms of the compounds described herein, wherein the prodrug is metabolized in vivo to produce a compound set forth herein, are included within the scope of the claims. In some cases, some of the compounds described herein can be prodrugs of another derivative or active compound.

[0466] Prodrugs are generally useful because, in some situations, they can be easier to administer than the parent drug. For example, they can be bioavailable by oral administration whereas the parent is not. Prodrugs can help enhance the cell permeability of a compound relative to the parent drug. Prodrugs can also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs can be designed to be reversible drug derivatives, used as modifiers to enhance the transport of a drug to a site-specific tissue or to increase the residence of a drug within a cell.

[0467] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, A.C.S. Symposium Series Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which disclosures are incorporated herein. According to another embodiment, the present disclosure provides methods of making the compounds defined above. These compounds can be synthesized using conventional techniques. Advantageously, these compounds can be conveniently synthesized from readily available starting materials.

[0468] Synthetic chemistry transformations and methodologies applicable in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2ndEd. (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, Ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0469] Therapeutic applications

[0470] The methods of administering the compounds or salts of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), or (Ila) discussed herein are useful in treating neuromuscular conditions and movement disorders. Examples of neuromuscular conditions include, but are not limited to, Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy 1, myotonic dystrophy 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb girdle muscular dystrophy, tendonitis, and carpal tunnel syndrome. Examples of movement disorders include, but are not limited to, muscle spasticity disorders, spasticity associated with multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, or cerebral palsy, or injury, or traumatic events such as stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, or amyotrophic lateral sclerosis. Also included are other conditions that can be responsive to inhibition of skeletal myosin II, skeletal troponin C, skeletal troponin I, skeletal nebulin, skeletal troponin T, skeletal regulatory light chain, skeletal myosin binding protein C, or skeletal actin.

[0471] In some embodiments, disclosed herein are methods of treating neuromuscular and movement disorders by administering a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), or (Ila). In some embodiments, disclosed herein are methods of treating neuromuscular and movement disorders by administering a compound or salt of Formula (III):

[0472]

[0473] or a salt thereof, wherein:

[0474] each Y is independently selected from the group consisting of C(R 3 ), N, and N+ (-O - );

[0475] A does not exist or is selected from -O- or -NR. 4 -、-CR 5 R 6 -、-C(O)-、-S-、-S(O)- and -S(O)2-;

[0476] R 1 Selected from:

[0477] C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -

[0478] N(R 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -

[0479] N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-

[0480] N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -

[0481] S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 Carbon rings and 3 to 10

[0482] The substituents of the heterocyclic ring, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0483] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R10 -

[0484] C(O)N(R 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-

[0485] OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -

[0486] S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 Substituents of -CN and -CN; or

[0487] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 carbon ring, wherein

[0488] 5- to 10-membered heterocyclic or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced; and

[0489] When A is -NR 4 - At that time, R 1 Additionally, it is selected from hydrogen, and when A is -C(O)-, R 1 Additionally selected from -N(R) 10 )2 and -OR 10 ;

[0490] When A does not exist, R 1 Further selection from halogens, -OR 10 -SR 10 -

[0491] N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 ,

[0492] N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2,

[0493] N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 ,

[0494] S(O)2R 10 , -NO2, and -CN;

[0495] each R 2 is independently selected from:

[0496] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2,

[0497] -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2,

[0498] N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 ,

[0499] -NO2, and -CN;

[0500] C 1-3 1-6alkyl, C 2-3 1-6alkenyl, and C 2-3 1-6alkynyl, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -

[0501] N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 ,

[0502] N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2,

[0503] N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 ,

[0504] S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and

[0505] C 3-10 arbon ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 ,

[0506] C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2,

[0507] OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 ,

[0508] S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN

[0509] each R 3 , R 5 , and R6 independently selected from the group consisting of:

[0510] hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and

[0511] C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -

[0512] OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; or

[0513] R 3 and R 1 together form a 5- to 10-membered heterocyclic ring or a C 5-10 carbocyclic ring, wherein the 5- to 10-membered heterocyclic ring or C 5-10 carbocyclic ring is optionally substituted with one or more R 9 ; or R 5 and R 1 together form a 3- to 10-membered heterocyclic ring or a saturated C 3-10 carbocyclic ring, wherein the 3- to 10-membered heterocyclic ring or saturated C 3-10 carbocyclic ring is optionally substituted with one or more R 9 ;

[0514] R 4 is independently selected from the group consisting of:

[0515] hydrogen; and

[0516] C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -

[0517] OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; or

[0518] R 4 and R 1 together form a 3- to 10-membered heterocyclic ring optionally substituted with one or more R 9 ;

[0519] each R 7 and R 8 is independently selected from the group consisting of:

[0520] halogen, -OR 10 , -SR 10 , -N(R 10 ;)2、-NO2、-CN、-CHF2、-

[0521] CF3, -CH2F, and optionally one or more independently selected from halogens, -OR 10 -

[0522] SR 10 -N(R) 10 2. C replaced by substituents of -NO2 and -CN 2-6 alkyl;

[0523] Each R 9 Selected independently from:

[0524] Halogen, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-

[0525] N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-

[0526] N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; and

[0527] C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -

[0528] C(O)N(R 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-

[0529] OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -

[0530] S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN;

[0531] each R 10 is independently selected from:

[0532] hydrogen;

[0533] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O,

[0534] =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl),

[0535] C 3-10 carbocycle, and 3- to 10-membered heterocycle; and

[0536] C 3-10 carbocycle, and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O,

[0537] O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and haloalkyl;

[0538] R 30 and R 31 are independently selected from R 10 or R 30 and R 31 together form a C3-7 carbocyclic or 3- to 7-membered heterocyclic ring, wherein C 3-7 carbocyclic and 3- to 7-membered heterocyclic ring are optionally substituted with one or more substituents independently selected from R 9 ; and

[0539] n is 0, 1, or 2;

[0540] p is 0, 1, or 2; and q is 0, 1, 2, 3, 4, or 5.

[0541] In some embodiments, disclosed herein are methods of treating neuromuscular and movement disorders by administering a compound or salt of Formula (III’):

[0542]

[0543] or a salt thereof, wherein:

[0544] each Y is independently selected from C(R 3 ), N, and N + (-O - );

[0545] A is selected from -O-, -NR 4 -, -CR 5 R 6 -, -C(O)-, -S-, -S(O)-, and -S(O)2-;

[0546] R 1 is selected from:

[0547] C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -

[0548] N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -

[0549] N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -

[0550] N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R10 -S(O)R 10 -

[0551] S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 Carbon rings and 3 to 10

[0552] The substituents of the heterocyclic ring, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced; and

[0553] C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -

[0554] C(O)N(R 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-

[0555] OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -

[0556] S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 Substituents of -CN and -CN; or

[0557] R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; or R 1 With R 5 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 9Replaced; or R 1 With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced; and

[0558] When A is -NR 4 - At that time, R 1 Additionally, it is selected from hydrogen, and when A is -C(O)-,

[0559] R 1 Additionally selected from -N(R) 10 )2 and -OR 10 ;

[0560] Each R 2 Selected independently from:

[0561] Halogen, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 2.

[0562] -N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-

[0563] N(R 10 )C(O)OR 10 ,-C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 ,

[0564] -NO2 and -CN; and

[0565] C 1-3 Alkyl, C 2-3 alkenyl and C 2-3 Alkyne groups, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -

[0566] N(R 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -

[0567] N(R 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-

[0568] N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -

[0569] S(O)2R 10 , -NO2, =O, =S, =N(R 10 Substituents of ) and -CN are substituted; each R 3 R 5 and R 6 Selected independently from:

[0570] Hydrogen, halogen, -OR 10 -SR 10 -N(R) 10 2. -NO2 and -CN; and

[0571] C 1-6 Alkyl groups, optionally composed of one or more elements independently selected from halogens, -

[0572] OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or

[0573] R 3 With R 1 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced; R 5 With R 1 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced; R 4 Selected independently from:

[0574] Hydrogen; and

[0575] C 1-6 Alkyl groups, optionally composed of one or more elements independently selected from halogens, -

[0576] OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN;

[0577] R 4 and R 1 together form a 3- to 10-membered heterocyclic ring, which is optionally substituted with one or more R 9 ;

[0578] each R 7 and R 8 is independently selected from:

[0579] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2,

[0580] CF3, -CH2F, and C 2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN;

[0581] each R 9 is independently selected from:

[0582] halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2,

[0583] N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2,

[0584] N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 ,

[0585] NO2, =O, =S, =N(R 10 ), and -CN; and

[0586] C 1-3 alkyl, C 2-3 alkenyl and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -

[0587] C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -

[0588] OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -

[0589] S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN;

[0590] each R 10 is independently selected from:

[0591] hydrogen;

[0592] C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halo, -CN, -OH, -SH, -NO2, -NH2, =O,

[0593] =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl),

[0594] C 3-10 carbocyclic and 3- to 10-membered heterocyclic ring; and

[0595] C 3-10carbon ring and 3- to 10-membered heterocycle, wherein each is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S,

[0596] O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbon ring, 3- to 10-membered heterocycle, and haloalkyl;

[0597] n is 0, 1, or 2;

[0598] p is 0, 1, or 2; and q is 0, 1, 2, 3, 4, or 5.

[0599] In certain embodiments, for a compound or salt of Formula (III) or (III’), at least one Y is N and the other is C(R + (-O - ). In certain embodiments, for a compound or salt of Formula (III) or (III’), one Y is N and the other is C(R 3 ). In certain embodiments, each Y is N.

[0600] In certain embodiments, for a compound or salt of Formula (III) or (III’), each Y is independently selected from C(R 3 ) and N, wherein at least one Y is N. In some embodiments, one Y is N and one Y is C(R 3 ). In some embodiments, one Y is N + (-O - ) and one Y is C(R 3 ). In some embodiments, each Y is N. In some embodiments, one Y is N, and one Y is N + (-O - ). In certain embodiments, for a compound or salt of Formula (III) or (III’), each Y is C(R 3 ).

[0601] In certain embodiments, for a compound or salt of any one of Formula (III) or (III’), A is selected from -O-, -NR 4 -, -CR 5 R 6 -, and -C(O)-. In some embodiments, A is selected from -O- and -NR 4In some implementations, A is -O-. In some implementations, A is -C(O)-. In some implementations, A is -NR. 4 -, such as -NH-.

[0602] In some embodiments, for any compound or salt of formula (III) or (III'),

[0603] R 1 C is optionally substituted by one or more substituents independently selected from the following 1-6 alkyl:

[0604] Halogen, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -C(O)OR 10 -OC(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 -CN, C 3-10 Carbon rings and 3- to 10-membered heterocycles, wherein the C 3-10 The carbon ring and the 3- to 10-membered heterocycle are each optionally separated by one or more R 9 Replaced. In some implementations, R 1 C is a C that is substituted by one or more substituents independently selected from the following 1-6 Alkyl groups: halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10

[0605] -C(O)OR 10 -OC(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R10 )2, -N(R 10 )C(O)OR 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 aromatic, carbocyclic, and 3- to 10-membered heterocyclic rings, wherein the C 3-10 aromatic, carbocyclic, and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 9 groups.

[0606] In certain embodiments, for a compound or salt of any one of Formula (III) or (III’),

[0607] R 1 is C 1-6 alkyl substituted with one or more substituents independently selected from halogen, -OR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -C(O)OR 10 , -OC(O)R 10 , -NO2, =O, =N(R 10 ), -CN, C 3-10 aromatic, carbocyclic, and 3- to 10-membered heterocyclic rings, wherein the C 3-10 aromatic, carbocyclic, and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 9 groups. In some embodiments, R 1 is C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 aromatic, carbocyclic, and 3- to 10-membered heterocyclic rings, wherein the C 3-10 aromatic, carbocyclic, and 3- to 10-membered heterocyclic rings are each optionally substituted with one or more R 9 groups. In some embodiments, R 1 is C 1-3 alkyl substituted with one or more substituents independently selected from halogen, -OR 10 , -N(R 10 )2, -NO2, =O, -CN, C 3-10carbocycle and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 9 In some embodiments, R 1 is C 1-3 alkyl substituted with one or more halo substituents. In some embodiments, R 1 is C 1-3 fluoroalkyl. In some embodiments, R 1 is selected from -CHF2, -CH2F, -CF3, -CH2CHF2, CH2CH2F, or -CH2CF3. In some embodiments, R 1 is CH2CN. In some embodiments, R 1 is not unsubstituted methyl. In some embodiments, R 1 is -NH2. In some embodiments, when A is -C(O)-, R 1 is -NH2. In some embodiments, R 1 is C 10 alkyl substituted with -OR 1-3 , wherein R 10 is C 1-3 alkyl substituted with one or more halo substituents. In some embodiments, R 1 is -CH2CH2-OR 10 , wherein R 10 is -CHF2or -CH3. In some embodiments, R 1 is C 1-3 alkyl substituted with =0. In some embodiments, R 1 is -C(O)-CH3. In some embodiments, R 1 is -CH3. In some embodiments, R 1 is selected from C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein the C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 9 In some embodiments, R 1 is C 3-10 carbocycle. In some embodiments, R 1 is C 3-5 carbocycle. In some embodiments, R 1 is cyclopropyl. In some embodiments, R 1 is C 1-3 alkyl substituted with one or more R 9 , wherein the 4- to 6-membered heterocycle is substituted with one or more R 1 In some embodiments, R The substituted methyl group of the 4 to 6-membered heterocycle.

[0608] In some embodiments, for any compound or salt of formula (III) or (III'), R 1 Selected from optionally substituted C3-C6 cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, dicyclopentyl, and spiropentyl, wherein any one of them is optionally substituted. In some embodiments, R 1 Selected from alkyl groups, such as methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl, sec-butyl, any of which may optionally be substituted. In some embodiments, R 1 Selected from: In some implementations, R 1 Selected from optional replacements

[0609] In some embodiments, for compounds or salts of formula (III) or (III'), R 1 With R 3 Together they form 5- to 10-membered heterocycles or C 5-10 Carbocyclic rings, wherein the 5- to 10-membered heterocyclic rings or C 5-10 The carbon ring is optionally divided by one or more R 9 Replaced. In some implementations, R 1 With R 3 Together they form C 5-10 Carbon rings or 5- to 10-membered heterocycles, such as C 5-6 Carbon rings or 5- to 6-membered heterocycles, for example:

[0610]

[0611] In some embodiments, for compounds or salts of formula (III) or (III'), R 1 With R 5 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbocyclic rings, wherein the 3- to 10-membered heterocyclic rings or saturated C 3-10 The carbon ring is optionally divided by one or more R 9 Replaced. In some implementations, R 1 With R 5 Together they form 3 to 10-membered heterocycles or saturated C 3-10 Carbon rings, for example:

[0612]

[0613]

[0614] In some embodiments, for compounds or salts of formula (III) or (III'), R 1With R 4 Together they form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally separated by one or more R 9 Replaced. In some implementations, R 1 With R 4 Together they form 3- to 10-membered heterocycles, for example:

[0615]

[0616] In some implementations, for any compound or salt of formula (III) or (III'), each R 2 Independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2, -CN and optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 2. C replaced by substituents of -NO2 and -CN 1-3 Alkyl group. In some embodiments, for compounds or salts of any of formula (III) or (III'), R 2 Selected from -Cl, -F, and -OH. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0.

[0617] In some embodiments, for compounds or salts of any of formula (III) or (III'), when R is present at one or two adjacent positions of the phenyl ring relative to the connection point with the rest of the molecule... 2 At that time, each neighboring R 2 Independently selected from halogens, -OR 10 -SR 10 -N(R) 10 2, -NO2, -CN and C 1-3 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, -NO2 and -CN substituents are substituted. In some embodiments, for compounds or salts of any of formula (III) or (III'), when R is present at one or two ortho positions of the phenyl ring relative to the connection point with the rest of the molecule. 2 At that time, each R 2 Independently selected from halogens, –OH, -OCH3, -OCF3, and C 1-3 Alkyl groups, which are optionally substituted with one or more substituents independently selected from halogens.

[0618] In some embodiments, for a compound or salt of either of Formula (III) or (III’), if R 2 is present at one or both ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule, then R 2 is not selected from a carbocycle or heterocycle. In some embodiments, for a compound or salt of either of Formula (III) or (III’), R 2 is not present at one or both ortho positions of the phenyl ring relative to the point of attachment to the rest of the molecule.

[0619] In certain embodiments, for a compound or salt of Formula (III) or (III’), each R 3 is selected from hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, and C 10 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 1-6 )2, -NO2, and -CN. In some embodiments, R 3 is hydrogen. In some embodiments, R 3 and R 1 together form a 5- to 6-membered heterocycle or C 5-6 carbocycle, wherein the 5- to 6-membered heterocycle or C 5-6 carbocycle is optionally substituted with one or more R 9 . In some embodiments, R 3 and R 1 together form a 5-membered heterocycle substituted with zero, one, or two methyl groups, for example:

[0620]

[0621] In certain embodiments, for a compound or salt of either of Formula (III) or (III’), R 4 is independently selected from hydrogen; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; or R 4 and R 1 together form a 3- to 10-membered heterocycle optionally substituted with one or more R 9 . In some embodiments, R 4 is hydrogen. In some embodiments, R 4methyl. In some embodiments, R 4 together with R 1 form a 4- to 5-membered heterocycle, which is optionally substituted with one or more R 9 , wherein R 9 is selected from methyl, -CH2F, -CHF2, -CF3, -F, -OCF3, and -OCHF2.

[0622] In certain embodiments, for a compound or salt of either of Formula (III) or (III’), each R 5 and R 6 is independently selected from hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2

[0623] , -CN, and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN. In some embodiments, R 1 together with R 5 forms a 3- to 10-membered heterocycle or a saturated C 3-10 carbocycle. In some embodiments, R 1 together with R 5 forms a cyclopropyl ring.

[0624] In certain embodiments, for a compound or salt of either of Formula (III) or (III’), each R 7 and R 8 is independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN, -CHF2, -CF3, -CH2F, and C 2-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN.

[0625] In certain embodiments, for a compound or salt of either of Formula (III) or (III’), each R 9 is independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =O, =S, -CN; and C 1-3alkyl, C 2-3 alkenyl, C 2-3 alkynyl, wherein each is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, -CN. In some embodiments, R 9 is halogen. In some embodiments, R 9 is -F. In some embodiments, R 9 is C 1-3 haloalkyl. In some embodiments, R 9 is C 1-3 alkyl substituted with one or more fluoro substituents. In some embodiments, R 9 is -CH2F, -CHF2, or -CF3. In some embodiments, R 9 is unsubstituted C 1-3 alkyl. In some embodiments, R 9 is methyl. In some embodiments, R 9 is -OR 10 . In some embodiments, R 9 is -OR 10 , and R 10 is C 1-3 haloalkyl. In some embodiments, R 9 is -OR 10 , and R 10 is -CH2F, -CHF2, or -CF3. In some embodiments, two R 9 groups together form a 3- to 10-membered heterocycle or C 10 carbocycle optionally substituted with one or more R 3-10 . In some embodiments, two R 9 groups together form a spirocyclic C 3-5 carbocycle substituted with one or more fluoro substituents. In some embodiments, two R 9 groups together form a spirocyclic cyclobutane substituted with two fluoro substituents.

[0626] In certain embodiments, for a compound or salt of any one of Formula (III) or (III’), each R 10 is independently selected from hydrogen; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C1-6 alkyl), C 3-10 alkyl, -S-C 3-10 alkyl, -S-C 1-6 alkyl, -S-C 1-6 alkyl, -S-C 1-6 alkyl, -S-C 1-6 alkyl, -S-C 1-6 alkyl, -S-C 3-10 alkyl, -S-C 10 -F.

[0627] In certain embodiments, for a compound or salt of any one of Formula (III) or (III’), n is 0.

[0628] In certain embodiments, for a compound or salt of any one of Formula (III) or (III’), p is 0.

[0629] In certain embodiments, for a compound or salt of any one of Formula (III) or (III’), R 1 -A is further selected from hydrogen. For example, the compound of Formula (III) or (III’) can be further selected from: or a salt thereof.

[0630] Presented herein are methods of treating neuromuscular and movement disorders by reducing skeletal muscle contraction. Treatment of a subject having a neuromuscular and movement disorder with a selective skeletal muscle fast-twitch (type II) myosin inhibitor of a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), (IIa), (III), or (III’) can reduce muscle breakdown by preventing excessive uncoordinated muscle contractions, thereby reducing muscle damage. Furthermore, the methods of the present disclosure can reduce muscle damage while minimizing the impact on the subject’s physical functioning. Preservation of function can be achieved both by limiting the level of damaging forces generated in type II fibers and by increasing reliance on healthier type I fibers. By inhibiting skeletal muscle myosin II, skeletal muscle contraction or uncoordinated muscle cramping can be reduced. In certain embodiments, the skeletal muscle myosin II inhibitor is a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), (IIa), (III), or (III’) disclosed herein.

[0631] In some embodiments, disclosed herein is a method of inhibiting muscle myosin II comprising administering to a subject in need thereof a compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), (Ila), (III), or (III’). In some embodiments, the compound or salt does not significantly inhibit cardiac muscle contraction. In some embodiments, the compound or salt reduces cardiac muscle force by less than 10%.

[0632] In some aspects, a method of treating a neuromuscular condition or movement disorder can comprise administering a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), (Ila), (III), or (III’) to inhibit skeletal muscle contraction. In some embodiments, the compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), (Ila), (III), or (III’) does not significantly inhibit cardiac muscle contraction. In some embodiments, cardiac muscle contraction is inhibited by 20% or less. In some embodiments, cardiac muscle contraction is inhibited by 15% or less. In some embodiments, cardiac muscle contraction is inhibited by 10% or less. In some embodiments, cardiac muscle contraction is inhibited by 9% or less. In some embodiments, cardiac muscle contraction is inhibited by 8% or less. In some embodiments, cardiac muscle contraction is inhibited by 7% or less. In some embodiments, cardiac muscle contraction is inhibited by 6% or less. In some embodiments, cardiac muscle contraction is inhibited by 5% or less. In some embodiments, cardiac muscle contraction is inhibited by 4% or less. In some embodiments, cardiac muscle contraction is inhibited by 3% or less. In some embodiments, cardiac muscle contraction is inhibited by 2% or less. In some embodiments, cardiac muscle contraction is inhibited by 1% or less.

[0633] Prior to and after treatment with a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), (Ila), (III), or (III’), a subject’s activities of daily living (ADL) or habitual physical activity can be monitored. ADL or habitual physical activity depends on the subject and can range from simple walking to extensive exercise, depending on the subject’s abilities and daily routine. The treatment options and dosages of skeletal muscle contraction inhibitors discussed herein can be individualized to the subject such that ADL and habitual physical activity remain unchanged.

[0634] In some aspects, a method of treating a neuromuscular disease or movement disorder can comprise administering a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') to inhibit skeletal muscle contraction. The amount of the compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') administered can be an amount required to reduce skeletal muscle contraction by 50%. The amount of the compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') administered can be less than an amount required to reduce skeletal muscle contraction by 50% relative to the subject's pre-treatment skeletal muscle contraction capacity. The compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') is administered in an amount to reduce skeletal muscle contraction by 5% to 45% relative to the subject's pre-treatment skeletal muscle contraction capacity. In some cases, the amount of the compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') administered can reduce skeletal muscle contraction by less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, or even less than 50% relative to the subject's pre-treatment skeletal muscle contraction capacity. In certain embodiments, the compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can be administered in an amount to reduce skeletal muscle contraction by 1% to 50% relative to the subject's pre-treatment skeletal muscle contraction capacity.

[0635] In some aspects, the method of treating a neuromuscular disease or movement disorder can comprise administering a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), (IIa), (III), or (III’) to inhibit type I skeletal muscle contraction. The amount of type I skeletal muscle contraction inhibitor administered can be an amount required to reduce type I skeletal muscle contraction by 20% relative to the subject’s pre-treatment type I skeletal muscle contraction capacity. The amount of type I skeletal muscle contraction inhibitor administered can be less than the amount required to reduce type I skeletal muscle contraction by 20% relative to the subject’s pre-treatment type I skeletal muscle contraction capacity. The type I skeletal muscle contraction inhibitor can be administered in an amount that reduces type I skeletal muscle contraction by 0.01% to 20% relative to the subject’s pre-treatment type I skeletal muscle contraction capacity. In some cases, the amount of inhibitor administered can reduce type I skeletal muscle contraction by less than 0.01%, less than 0.1%, less than 0.5%, less than 1%, less than 5%, less than 10%, less than 15%, or less than 20% relative to the subject’s pre-treatment type I skeletal muscle contraction capacity. In certain embodiments, the inhibitor can be administered in an amount that reduces type I skeletal muscle contraction by 0.01% to 20% relative to the subject’s pre-treatment type I skeletal muscle contraction capacity.

[0636] In some aspects, the method of treating a neuromuscular disease or movement disorder can comprise administering a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II’), (IIa), (III), or (III’) to inhibit type II skeletal muscle contraction. The amount of type II skeletal muscle contraction inhibitor administered can be an amount required to reduce type II skeletal muscle contraction by 90% relative to the subject’s pre-treatment type II skeletal muscle contraction capacity. The amount of type II skeletal muscle contraction inhibitor administered can be less than the amount required to reduce type II skeletal muscle contraction by 90% relative to the subject’s pre-treatment type II skeletal muscle contraction capacity. The type II skeletal muscle contraction inhibitor can be administered in an amount that reduces type II skeletal muscle contraction by 5% to 75% relative to the subject’s pre-treatment type II skeletal muscle contraction capacity. In some cases, the amount of inhibitor administered can reduce type II skeletal muscle contraction by less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 35%, less than 40%, less than 45%, less than 50%, less than 55%, less than 60%, less than 65%, less than 70%, less than 75%, less than 80%, less than 85%, or even less than 90% relative to the subject’s pre-treatment type II skeletal muscle contraction capacity. In certain embodiments, the inhibitor can be administered in an amount that reduces type II skeletal muscle contraction by 1% to 50% relative to the subject’s pre-treatment type II skeletal muscle contraction capacity.

[0637] In some aspects, methods of treating contraction-induced injury in skeletal muscle fibers can comprise administering a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') to inhibit skeletal muscle contraction and / or skeletal muscle myosin II. In certain embodiments, the inhibitor does not significantly inhibit cardiac muscle contraction.

[0638] In certain embodiments, the contraction-induced injury in skeletal muscle fibers is from involuntary skeletal muscle contraction. Involuntary skeletal muscle contraction can be associated with a neuromuscular disease or a spastic-related disease. In certain embodiments, the contraction-induced injury in skeletal muscle fibers can be from voluntary skeletal muscle contraction, such as sports.

[0639] In some aspects, methods of treating metabolic myopathy, such as McCardle Syndrome, can comprise administering a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III').

[0640] In certain embodiments, administration of a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') to a subject modulates one or more biomarkers associated with muscle contraction. Examples of biomarkers include, but are not limited to, creatine kinase (CK), troponin T (TnT), troponin C (TnC), troponin I (Tnl), pyruvate kinase (PK), lactate dehydrogenase (LDH), myoglobin, isoforms of Tnl (e.g., Tnl of cardiac muscle, skeletal muscle slow muscle, skeletal muscle fast muscle), and inflammatory markers (IL-1, IL-6, IL-4, TNF-a). Biomarkers can also include measures of muscle inflammation, such as edema. Levels of the biomarkers described herein can increase following administration of the inhibitor relative to pre-treatment levels of the biomarker. Alternatively, levels of the biomarker can decrease following administration of the inhibitor relative to pre-treatment levels of the biomarker. Modulation of one or more biomarkers with the inhibitors described herein can be indicative of treatment of a neuromuscular disease, such as those described herein.

[0641] CK levels increase during activity compared to when the subject is inactive (e.g., sleeping), therefore CK is a potential measure for assessing skeletal muscle breakdown caused by skeletal muscle contraction. In some embodiments, a compound or salt of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') may be administered to the subject prior to mild, moderate, or vigorous activity to reduce or prevent skeletal muscle breakdown due to activity. Moderate to vigorous activity may depend on the subject's ability and may include physical activity that increases the heart rate by at least 20% or more relative to the subject's resting heart rate, such as approximately 50% or more. Examples of moderate to vigorous activity include walking, running, weightlifting, cycling, swimming, hiking, etc.

[0642] In certain embodiments, a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') is administered prior to, during, or after moderate or strenuous activity to reduce or prevent breakdown of skeletal muscle from the activity. The compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') can reduce the subject's CK level relative to an untreated subject performing the same activity. The CK level can be measured in the subject's peripheral blood during or after the activity. Administration of the inhibitor described herein can reduce the subject's CK level by 5% to 90% relative to an untreated subject performing the same activity, thereby reducing or preventing breakdown of skeletal muscle from the activity. Administration of the inhibitor described herein can modulate the CK level by about 5% to about 90% relative to an untreated subject performing the same activity, thereby reducing or preventing breakdown of skeletal muscle from the activity. Administration of the inhibitor described herein can reduce the CK level by at least about 5% relative to an untreated subject performing the same activity, thereby reducing or preventing breakdown of skeletal muscle from the activity. Administration of the inhibitor described herein can modulate the CK level by at most about 90% relative to an untreated subject performing the same activity. Administration of the inhibitor described herein can reduce the CK level by about 5% to about 15%, about 5% to about 25%, about 5% to about 35%, about 5% to about 45%, about 5% to about 55%, about 5% to about 65%, about 5% to about 75%, about 5% to about 85%, about 5% to about 90%, about 15% to about 25%, about 15% to about 35%, about 15% to about 45%, about 15% to about 55%, about 15% to about 65%, about 15% to about 75%, about 15% to about 85%, about 15% to about 90%, about 25% to about 35%, about 25% to about 45%, about 25% to about 55%, about 25% to about 65%, about 25% to about 75%, about 25% to about 85%, about 25% to about 90%, about 35% to about 45%, about 35% to about 55%, about 35% to about 65%, about 35% to about 75%, about 35% to about 85%, about 35% to about 90%, about 45% to about 55%, about 45% to about 65%, about 45% to about 75%, about 45% to about 85%, about 45% to about 90%, about 55% to about 65%, about 55% to about 75%, about 55% to about 85%, about 55% to about 90%, about 65% to about 75%, about 65% to about 85%, about 65% to about 90%, about 75% to about 85%, about 75% to about 90%, or about 85% to about 90% relative to an untreated subject performing the same activity, thereby reducing or preventing breakdown of skeletal muscle from the activity.Administration of the inhibitors described herein can modulate CK levels by about 5%, about 15%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, or about 90% relative to untreated subjects performing the same activity, thereby reducing or preventing breakdown of skeletal muscle due to the activity.

[0643] Administration of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II’), (Ila), (III), or (III’) to a subject can modulate the level of an inflammatory marker, e.g., decrease the level of one or more inflammatory markers relative to an untreated subject or a subject prior to treatment. The level of an inflammatory marker can be measured in the peripheral blood of a subject. Examples of inflammatory markers can include, but are not limited to, IL-1, IL-6, and TNF-a. An inflammatory marker can also be a measure of a condition such as edema, which can be measured using magnetic resonance imaging. The level of an inflammatory marker in the peripheral blood can increase following administration of an inhibitor relative to the pre-treatment level of the inflammatory marker in the subject. Alternatively, the level of an inflammatory marker in the peripheral blood can decrease following administration of an inhibitor relative to the pre-treatment level of the inflammatory marker in the subject. Administration of an inhibitor described herein can modulate the level of an inflammatory marker by 5% to 90% relative to the pre-treatment level of the inflammatory marker in the subject. In some cases, the level of an inflammatory marker can be modulated by about 5% to about 90% relative to the pre-treatment level of the inflammatory marker in the subject. In some cases, the level of an inflammatory marker can be modulated by at least about 5% relative to the pre-treatment level of the inflammatory marker in the subject. In some cases, the level of an inflammatory marker can be modulated by at most about 90% relative to the pre-treatment level of the inflammatory marker in the subject. In some cases, the level of an inflammatory marker can be modulated by about 5% to about 15%, about 5% to about 25%, about 5% to about 35%, about 5% to about 45%, about 5% to about 55%, about 5% to about 65%, about 5% to about 75%, about 5% to about 85%, about 5% to about 90%, about 15% to about 25%, about 15% to about 35%, about 15% to about 45%, about 15% to about 55%, about 15% to about 65%, about 15% to about 75%, about 15% to about 85%, about 15% to about 90%, about 25% to about 35%, about 25% to about 45%, about 25% to about 55%, about 25% to about 65%, about 25% to about 75%, about 25% to about 85%, about 25% to about 90%, about 35% to about 45%, about 35% to about 55%, about 35% to about 65%, about 35% to about 75%, about 35% to about 85%, about 35% to about 90%, about 45% to about 55%, about 45% to about 65%, about 45% to about 75%, about 45% to about 85%, about 45% to about 90%, about 55% to about 65%, about 55% to about 75%, about 55% to about 85%, about 55% to about 90%, about 65% to about 75%, about 65% to about 85%, about 65% to about 90%, about 75% to about 85%, about 75% to about 90%, or about 85% to about 90% relative to the pre-treatment level of the inflammatory marker in the subject.In some cases, the level of the inflammatory marker can be modulated by about 5%, about 15%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, or about 90% relative to the pre-treatment level of the inflammatory marker in the subject.

[0644] Administration of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') to a subject can modulate the level of circulating skeletal fast myosin I (fS-TnI). The level of fS-TnI can be measured in peripheral blood. The level of fS-TnI in peripheral blood can be increased following administration of an inhibitor relative to the pre-treatment level of fS-TnI in the subject. Alternatively, the level of fS-TnI in peripheral blood can be decreased following administration of an inhibitor relative to the pre-treatment level of fS-TnI in the subject. Administration of an inhibitor described herein can modulate the level of fS-TnI by 5% to 90% relative to the pre-treatment level of fS-TnI in the subject. In some cases, the level of fS-TnI can be modulated by at least about 5% relative to the pre-treatment level of fS-TnI in the subject. In some cases, the level of fS-TnI can be modulated by at most about 90% relative to the pre-treatment level of fS-TnI in the subject. In some cases, the level of fS-TnI can be modulated by about 5% to about 15%, about 5% to about 25%, about 5% to about 35%, about 5% to about 45%, about 5% to about 55%, about 5% to about 65%, about 5% to about 75%, about 5% to about 85%, about 5% to about 90%, about 15% to about 25%, about 15% to about 35%, about 15% to about 45%, about 15% to about 55%, about 15% to about 65%, about 15% to about 75%, about 15% to about 85%, about 15% to about 90%, about 25% to about 35%, about 25% to about 45%, about 25% to about 55%, about 25% to about 65%, about 25% to about 75%, about 25% to about 85%, about 25% to about 90%, about 35% to about 45%, about 35% to about 55%, about 35% to about 65%, about 35% to about 75%, about 35% to about 85%, about 35% to about 90%, about 45% to about 55%, about 45% to about 65%, about 45% to about 75%, about 45% to about 85%, about 45% to about 90%, about 55% to about 65%, about 55% to about 75%, about 55% to about 85%, about 55% to about 90%, about 65% to about 75%, about 65% to about 85%, about 65% to about 90%, about 75% to about 85%, about 75% to about 90%, or about 85% to about 90% relative to the pre-treatment level of fS-TnI in the subject. In some cases, the level of fS-TnI can be modulated by about 5%, about 15%, about 25%, about 35%, about 45%, about 55%, about 65%, about 75%, about 85%, or about 90% relative to the pre-treatment level of fS-TnI in the subject.

[0645] Subtypes of troponin can be measured in a subject before and after administration of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III'). Inhibition of skeletal muscle contraction can not inhibit some subtypes of troponin, such as cardiac troponin I (cTnl) or skeletal slow-twitch troponin I (ssTnl). In some cases, inhibition of skeletal muscle contraction can not significantly inhibit cTnl or ssTnl. As used herein, with respect to cTnl or ssTnl, the word not significantly means less than a 10%, less than an 8%, less than a 6%, less than a 4%, less than a 2%, less than a 1%, less than a 0.5%, or even less than a 0.1% reduction in cTnl or ssTnl relative to cTnl or ssTnl prior to administration of the inhibitor.

[0646] Administration of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II’), (Ila), (III), or (III’) can reduce involuntary muscle contractions. Involuntary muscle contractions can be reduced by 20% to 90% relative to involuntary muscle contractions prior to inhibitor administration. In some cases, involuntary muscle contractions can be reduced by at least about 20% relative to involuntary muscle contractions prior to treatment. In some cases, involuntary muscle contractions can be reduced by at most about 90% relative to involuntary muscle contractions prior to treatment. In some cases, involuntary muscle contractions can be reduced by about 20% to about 25%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 70%, about 20% to about 75%, about 20% to about 80%, about 20% to about 85%, about 20% to about 90%, about 25% to about 30%, about 25% to about 40%, about 25% to about 50%, about 25% to about 70%, about 25% to about 75%, about 25% to about 80%, about 25% to about 85%, about 25% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 70%, about 30% to about 75%, about 30% to about 80%, about 30% to about 85%, about 30% to about 90%, about 40% to about 50%, about 40% to about 70%, about 40% to about 75%, about 40% to about 80%, about 40% to about 85%, about 40% to about 90%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, about 50% to about 85%, about 50% to about 90%, about 70% to about 75%, about 70% to about 80%, about 70% to about 85%, about 70% to about 90%, about 75% to about 80%, about 75% to about 85%, about 75% to about 90%, about 80% to about 85%, about 80% to about 90%, or about 85% to about 90% relative to involuntary muscle contractions prior to treatment. In some cases, involuntary muscle contractions can be reduced by about 20%, about 25%, about 30%, about 40%, about 50%, about 70%, about 75%, about 80%, about 85%, or about 90% relative to involuntary muscle contractions prior to treatment.

[0647] A compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can be used to improve the activities of daily living (ADL) or habitual physical activity of a subject, as mature, fully functional, undamaged muscle can be restored. Examples of ADL or habitual activities include, but are not limited to, stair climbing, time to get out of bed, timed get up from a chair, usual walking speed, North Star Dynamic Assessment, incremental / endurance shuttle walk, and 6-minute walk distance test. The level or ability of ADL or habitual physical activity can be measured before and after administration of a skeletal muscle inhibitor. Inhibiting skeletal muscle contraction can not affect ADL or habitual physical activity. In some cases, inhibiting skeletal muscle contraction can not appreciably affect ADL or habitual physical activity. As used herein, the phrase appreciably, with respect to ADL or habitual physical activity, means a decrease in the level of ADL or habitual activity of less than 20%, less than 15%, less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1%, relative to the ADL or habitual physical activity prior to administration of the inhibitor. Skeletal muscle contraction or force in a subject can be measured before and after administration of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III'). Such measurements can be made to generate a dose response curve for a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III'). The dose of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can be adjusted by about 5% to 50% relative to a dose that reduces type II skeletal muscle contraction by 90%. In some cases, the dose of a skeletal muscle contraction inhibitor can be adjusted by at least about 5% relative to a dose that reduces type II skeletal muscle contraction by 90%. In some cases, the dose of a skeletal muscle contraction inhibitor can be adjusted by at most about 50% relative to a dose that reduces type II skeletal muscle contraction by 90%.In some cases, relative to a dose that reduces type II skeletal muscle contraction by 90%, the dose of skeletal muscle contraction inhibitor can be adjusted by approximately 5% to approximately 10%, approximately 5% to approximately 15%, approximately 5% to approximately 20%, approximately 5% to approximately 25%, approximately 5% to approximately 30%, approximately 5% to approximately 35%, approximately 5% to approximately 40%, approximately 5% to approximately 50%, approximately 10% to approximately 15%, approximately 10% to approximately 20%, approximately 10% to approximately 25%, approximately 10% to approximately 30%, approximately 10% to approximately 35%, approximately 10% to approximately 40%, approximately 10% to approximately 50%, approximately 15% to approximately 20%, approximately 15% to ... % to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 50%, about 35% to about 40%, about 35% to about 50%, or about 40% to about 50%. In some cases, the dose of a skeletal muscle contraction inhibitor may be adjusted by approximately 10%, 12%, 15%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative to a dose that reduces type II skeletal muscle contraction by 90%. Skeletal muscle contraction can be measured before and after administration of the skeletal muscle contraction inhibitor by muscle strength testing using surface electrodes after nerve stimulation (e.g., plantar flexion after peroneal nerve stimulation of the leg), isolated limb assay, heart rate monitor or activity monitor, or equivalent methods.

[0648] Cardiac muscle force or cardiac muscle contraction can be measured in a subject before and after administration of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III'). Inhibition of skeletal muscle contraction can not inhibit cardiac muscle contraction or cardiac muscle force. In some embodiments, inhibition of skeletal muscle contraction can not significantly inhibit cardiac muscle contraction. In certain embodiments with respect to cardiac muscle contraction, the term not significantly means a decrease in cardiac muscle force of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% relative to the cardiac muscle force prior to administration of the inhibitor. Cardiac muscle force or cardiac muscle contraction in a subject after administration of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can be within 0.1% to 10% of the cardiac muscle contraction or cardiac muscle force prior to administration of the inhibitor. In some embodiments, administration of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can inhibit skeletal muscle contraction and cardiac muscle contraction or cardiac muscle force. In some embodiments, the decrease in cardiac muscle force is more than 0.1%, more than 0.5%, more than 1%, more than 2%, more than 4%, more than 6%, more than 8%, or more than 10%. In some embodiments, the decrease in skeletal muscle contraction and cardiac muscle contraction is described by the ratio of one to the other. For example, in some embodiments, the ratio of the decrease in skeletal muscle contraction to the decrease in cardiac muscle contraction is about 1:1 to about 100:1, about 2:1 to about 50:1, about 3:1 to about 40:1, about 4:1 to about 30:1, about 5:1 to about 20:1, about 7:1 to about 15:1, or about 8:1 to about 12:1. Cardiac muscle force or cardiac muscle contraction can be measured using echocardiography (fraction shortening) or other equivalent tests.

[0649] Tidal volume in the lungs of a subject can be measured before and after administration of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III'). Administration can not inhibit tidal volume in the lungs. In some cases, administration can not significantly inhibit tidal volume in the lungs. In certain embodiments with respect to tidal volume in the lungs, the term not significantly means a decrease in tidal volume in the lungs of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% relative to the tidal volume in the lungs prior to administration of the inhibitor. Tidal volume in the lungs of a subject can be measured using a forced expiratory volume in one second test (FEVi) or forced vital capacity test (FVC) or equivalent test thereof.

[0650] Smooth muscle contraction in a subject can be measured before and after administration of a skeletal muscle contraction inhibitor. Inhibiting skeletal muscle contraction can not inhibit smooth muscle contraction. In some cases, inhibiting skeletal muscle contraction can not significantly inhibit smooth muscle contraction. As used herein, the word not significantly, with respect to smooth muscle contraction, means less than a 10%, less than an 8%, less than a 6%, less than a 4%, less than a 2%, less than a 1%, less than a 0.5%, or even less than a 0.1% decrease in smooth muscle contraction relative to the subject's smooth muscle contraction prior to administration of the inhibitor. Smooth muscle contraction in a subject can be assessed by measuring the subject's blood pressure.

[0651] Neuromuscular coupling in a subject can be measured before and after administration of a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III'). Inhibiting skeletal muscle contraction with an inhibitor described herein can not impair neuromuscular transmission, neurotransmitter release, or electrical depolarization of a subject's skeletal muscle. In some cases, inhibiting skeletal muscle contraction can not significantly impair neuromuscular coupling in a subject. As used herein, the word not significantly, with respect to neuromuscular coupling, means less than a 10%, less than an 8%, less than a 6%, less than a 4%, less than a 2%, less than a 1%, less than a 0.5%, or even less than a 0.1% decrease in the level of neuromuscular coupling in a subject relative to the level of neuromuscular coupling in the subject prior to administration of the inhibitor. Neuromuscular coupling in a subject can be assessed by measuring the nerve-induced electrical depolarization of skeletal muscle by using surface or needle electrodes, and recording the electrical activity produced by the skeletal muscle after electrical or voluntary stimulation using electromyography (EMG).

[0652] In some aspects, a method of treating a neuromuscular disease or movement disorder can comprise administering a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III'), wherein the compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') can inhibit myosin ATPase activity, native skeletal muscle myofibril ATPase (calcium regulated), or reconstituted S1 with actin, myosin, and troponin. An in vitro assay can be used to test a test compound or inhibitor for effects on myosin ATPase activity. Test compounds can be screened to assess their inhibitory activity on muscle contraction. Inhibitory activity can be determined using a spectrophotometric assay to determine actin-activated ATPase activity. Rabbit muscle myosin subfragment 1 (S1) can be mixed with polymerized actin and dispersed into nucleotide-free assay plate wells. Test compounds can then be added to the wells with a needle array. The reaction can be initiated with MgATP. The amount of ATP consumed in the test vessel over a defined time period can be compared to the amount of ATP consumed in a control vessel. The defined time period can be 5 minutes to 20 minutes. The amount of ATP consumed can be determined by direct or indirect assay. Test compounds that reproducibly and potently inhibit myosin S1 ATPase activity can be further evaluated in a dose response assay to determine the compound's ex vivo IC50 on dissected muscle. The assay can indirectly measure ATPase activity by coupling myosin to pyruvate kinase and lactate dehydrogenase to provide a spectrophotometric detection method at 340 nm based on the conversion of NADH to NAD+ driven by ADP accumulation. In some cases, a test compound can be selected as a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') if the ATP consumption in the test vessel is reduced by at least 20% compared to the control vessel. In a kinetic assay, a test compound can be selected when the inhibition of NAD+ generation is enhanced by at least 20%.

[0653] In some cases, the selected inhibitor or test compound can not inhibit cardiac myosin S1 ATPase in an in vitro assay. In some cases, cardiac myosin S1 ATPase or cardiac myofibrils or reconstituted systems can be inhibited by less than 10%, less than 8%, less than 5%, less than 3%, less than 2%, less than 1%, or less than 0.5% when a test compound or a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') is tested in an in vitro assay.

[0654] Test compounds can be tested for skeletal muscle contraction on skinned fibers. Single skeletal muscle fibers treated to remove membranes and allow direct activation of contraction upon calcium application can be used. The inhibitor compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') can inhibit contraction of the single skeletal muscle fiber by about 5% to about 90% relative to the value before treatment or untreated control single skeletal muscle. The inhibitor can inhibit contraction of the single skeletal muscle fiber by at least about 5% relative to the value before treatment or untreated control single skeletal muscle fiber. The inhibitor can inhibit contraction of the single skeletal muscle fiber by at most about 90% relative to the value before treatment or untreated control single skeletal muscle fiber. The inhibitor can inhibit contraction of the single skeletal muscle fiber by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40%, about 5% to about 50%, about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90% relative to the ability before treatment or untreated control single skeletal muscle fiber. The inhibitor can inhibit contraction of the single skeletal muscle fiber by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to the ability before treatment or untreated control single skeletal muscle fiber.

[0655] The inhibitor compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (IIa), (III), or (III') can inhibit contraction of a single skeletal muscle by about 5% to about 90% relative to the value prior to treatment or untreated control single skeletal muscle. The inhibitor can inhibit contraction of a single skeletal muscle by at least about 5% relative to the value prior to treatment or untreated control single skeletal muscle. The inhibitor can inhibit contraction of a single skeletal muscle by at most about 90% relative to the value prior to treatment or untreated control single skeletal muscle. The inhibitor can inhibit contraction of a single skeletal muscle by about 5% to about 10%, about 5% to about 20%, about 5% to about 30%, about 5% to about 40

[0656] about 5% to about 60%, about 5% to about 70%, about 5% to about 80%, about 5% to about 90%, about 10% to about 20%, about 10% to about 30%, about 10% to about 40%, about 10% to about 50%, about 10% to about 60%, about 10% to about 70%, about 10% to about 80%, about 10% to about 90%, about 20% to about 30%, about 20% to about 40%, about 20% to about 50%, about 20% to about 60%, about 20% to about 70%, about 20% to about 80%, about 20% to about 90%, about 30% to about 40%, about 30% to about 50%, about 30% to about 60%, about 30% to about 70%, about 30% to about 80%, about 30% to about 90%, about 40% to about 50%, about 40% to about 60%, about 40% to about 70%, about 40% to about 80%, about 40% to about 90%, about 50% to about 60%, about 50% to about 70%, about 50% to about 80%, about 50% to about 90%, about 60% to about 70%, about 60% to about 80%, about 60% to about 90%, about 70% to about 80%, about 70% to about 90%, or about 80% to about 90% relative to the ability prior to treatment or untreated control single skeletal muscle. The inhibitor can inhibit contraction of a single skeletal muscle by about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% relative to the ability prior to treatment or untreated control single skeletal muscle.

[0657] The effects of a test compound on slow type I skeletal muscle fibers, cardiac muscle bundles, or pulmonary muscle fibers can be assessed. A test compound or inhibitor compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can be selected such that it does not significantly modulate the function of slow type I skeletal muscle fibers, cardiac muscle bundles, or pulmonary muscle fibers, and is specific for type II skeletal muscle. As used herein, the term "significantly modulate" can refer to a decrease in the contractile capacity of the muscle of less than 10%, less than 8%, less than 6%, less than 4%, less than 2%, less than 1%, less than 0.5%, or even less than 0.1% relative to the muscle force / contraction prior to inhibitor administration, following inhibitor administration.

[0658] In some aspects, a method of treating a neuromuscular disease or movement disorder can comprise administering to a subject in need thereof a compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') wherein the compound of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') or salt thereof reduces skeletal muscle contraction by 5% to 90% in an ex vivo assay. The ex vivo assay used can be a mouse model. The mouse model used can be a dystrophic mouse model, such as an mdx mouse. The dystrophin gene of the mdx mouse has a point mutation that changes the amino acid encoding glutamine to threonine, resulting in a non-functional dystrophin protein that leads to increased muscle impairment and muscle weakness. The extensor digitorum longus muscle can be dissected from the mdx mouse and mounted on a lever arm. The muscle can be bathed in oxygenated Kreb's solution to maintain muscle function. The test compound or compound or salt of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') can be applied to the muscle. An isometric (fixed length) contraction step can then be performed, in which the muscle is stimulated with a series of electrical pulses. A concentric (lengthening) contraction step can be performed, in which the muscle is stretched 10%, 15%, 20%, 25%, or 30% greater than its resting length while at rest or stimulated with electrical pulses. In some embodiments, the concentric contraction step is repeated 2 to 50 times. In some embodiments, the concentric contraction step is repeated 2 to 40 times. In some embodiments, the concentric contraction step is repeated 2 to 30 times. In some embodiments, the concentric contraction step is repeated 2 to 20 times. In some embodiments, the concentric contraction step is repeated 2 to 10 times. In some embodiments, the concentric contraction step is repeated 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 times to cause muscle fiber damage. In some embodiments, the electrical pulses can have a frequency of about 1 Hz to about 500 Hz. In some embodiments, the electrical pulses can have a frequency of about 1 Hz to about 400 Hz. In some embodiments, the electrical pulses can have a frequency of about 1 Hz to about 300 Hz. In some embodiments, the electrical pulses can have a frequency of about 1 Hz to about 200 Hz. In some embodiments, the electrical pulses can have a frequency of about 1 Hz to about 100 Hz. The electrical pulses can have a frequency of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, or 150 Hz. The series of electrical pulses can include individual pulses of different frequencies. The time period for each pulse of the series of electrical pulses can be between 0.1 seconds to 0.5 seconds for each pulse.The time of each pulse can be 0.1, 0.2, 0.3, 0.35, 0.4, or 0.5 seconds. Muscle membrane damage can also be measured by incubating the muscle in active orange after isometric or eccentric contractions. Active orange is a fluorescent dye that is taken up by muscle fibers with membrane damage. The number or proportion of dye-positive fibers can then be quantified by histology. A test compound can be selected as a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') when the test force drop and / or the proportion of dye-positive fibers is at least 20% less than the control force drop and / or dye uptake.

[0659] Using a set of isometric or eccentric contractions, the force generated by the muscle can be measured. The change in force generated by the muscle before and after a set of isometric or eccentric contractions can be calculated as the test force drop and compared to the change in force generated by muscle contraction from the first pulse to the last pulse in a control sample that was not exposed to the test compound (control force drop). The force drop can be used as a proxy for muscle damage, and a test compound can be selected as an inhibitor compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') when the test force drop is at least 20% less than the control force drop.

[0660] Pharmaceutical formulations

[0661] The compositions and methods described herein can be considered to be useful as a pharmaceutical composition for administration to a subject in need thereof. The pharmaceutical composition can comprise at least a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, stabilizers, dispersing agents, suspending agents, and / or thickening agents.

[0662] Pharmaceutical compositions of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries. The formulations can be modified depending on the selected route of administration. Pharmaceutical compositions comprising a compound, salt, or conjugate can be manufactured by, for example, lyophilizing the compound, salt, or conjugate, mixing, dissolving, emulsifying, encapsulating, or entrapping the conjugate. The pharmaceutical compositions can also comprise the compound, salt, or conjugate in free base form or in a pharmaceutically acceptable salt form.

[0663] Methods for formulating a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can include formulating any compound, salt, or conjugate with one or more inert, pharmaceutically acceptable excipients or carriers to form a solid, semisolid, or liquid composition. Solid compositions can include, for example, powders, tablets, dispersible granules, and capsules, and in certain aspects, the solid compositions further comprise nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and other pharmaceutically acceptable additives. Alternatively, the compound, salt, or conjugate can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0664] Pharmaceutical compositions of a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can comprise at least one active ingredient (e.g., a compound, salt, or conjugate and other agents). The active ingredient can be encased within microcapsules such as those prepared by coacervation techniques or by interfacial polymerization (for example, hydroxymethylcellulose or gelatin microcapsules and poly-(methylmethacrylate) microcapsules, respectively), colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules), or macroemulsions.

[0665] Compositions and formulations can be sterilized. Sterilization can be accomplished by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents into the compositions.

[0666] Compositions comprising a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can be formulated for administration as an injection. Non-limiting examples of formulations for injection can include sterile suspensions, solutions or emulsions in oily or aqueous vehicles. Suitable oily vehicles can include, but are not limited to, lipophilic solvents or vehicles, such as fatty oils, or synthetic fatty acid esters, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. The suspension can also contain suitable stabilizers. The injectable formulations can be formulated for bolus or continuous infusion. Alternatively, the compositions can be lyophilized or in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0667] For parenteral administration, the compounds or salts of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') can be formulated in unit- dose injectable forms (e.g., solutions, suspensions, emulsions) with pharmaceutically-acceptable parentally-acceptable vehicles. Such vehicles can be inherently non-toxic and non-therapeutic. Vehicles can be aqueous, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Non-aqueous vehicles can also be used, e.g., fixed oils and ethyl oleate. Liposomes can be used as vehicles. Vehicles can contain minor amounts of additives such as substances that enhance isotonicity and chemical stability (e.g., buffers and preservatives).

[0668] In one embodiment, the present application relates to methods and compositions of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') that are formulated for oral delivery to a subject in need thereof. In one embodiment, the composition is formulated so as to deliver one or more pharmaceutically active agents through the mucosal layer in the mouth or esophagus to the subject. In another embodiment, the composition is formulated so as to deliver one or more pharmaceutically active agents through the mucosal layer in the stomach and / or intestines to the subject.

[0669] In one embodiment, the composition of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') is provided in a modified release dosage form. Suitable modified release dosage vehicles include, but are not limited to, hydrophilic or hydrophobic matrix devices, water-soluble barrier-coatings, enteric coatings, osmotic devices, multiple- unit devices, and combinations thereof. The composition can also include non-release controlling excipients.

[0670] In another embodiment, the composition of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') is provided in an enteric-coated dosage form. These enteric-coated dosage forms can also include non-release controlling excipients. In one embodiment, the composition is in the form of enteric-coated granules as a controlled release capsule for oral administration. The composition can further include cellulose, disodium hydrogen phosphate, hydroxypropyl cellulose, hypromellose, lactose, mannitol, or sodium lauryl sulfate. In another embodiment, the composition is in the form of enteric-coated pellets as a controlled release capsule for oral administration. The composition can further include glyceryl monostearate 40-50, hydroxypropyl cellulose, hypromellose, magnesium stearate, methacrylic acid copolymer type C, polysorbate 80, sugar spheres, talc, and triethyl citrate.

[0671] In another embodiment, the composition of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') is an enteric controlled release tablet for oral administration. The composition can further comprise palmitic wax, crospovidone, diacetylated monoglycerides, ethyl cellulose, hydroxypropyl cellulose, hypromellose phthalate, magnesium stearate, mannitol, sodium hydroxide, sodium stearyl fumarate, talc, titanium dioxide, and yellow ferric oxide.

[0672] Sustained release articles comprising a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can also be prepared. Examples of sustained release articles can include semipermeable matrices of solid hydrophobic polymer, which can contain the compound, salt, or conjugate, and these matrices can be in the form of shaped articles (e.g., films or microcapsules). Examples of sustained release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactic acid, copolymer of L-glutamic acid and L- glutamic acid ethyl ester, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT® TM (i.e., injectable microspheres composed of lactic acid-glycolic copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.

[0673] Pharmaceutical formulations comprising a compound or salt of Formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can be prepared for storage by mixing the compound, salt, or conjugate with a pharmaceutically acceptable carrier, excipient, and / or stabilizer. The formulation can be a lyophilized formulation or an aqueous solution. Acceptable carriers, excipients, and / or stabilizers can be nontoxic to recipients at the dosages and concentrations employed. Acceptable carriers, excipients, and / or stabilizers can include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives, polypeptides; proteins such as serum albumin or gelatin; hydrophilic polymers; amino acids; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes; and / or nonionic surfactants or polyethylene glycol.

[0674] In another embodiment, the composition of formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can further comprise calcium stearate, crospovidone, hydroxypropyl methylcellulose, iron oxide, mannitol, methacrylic acid copolymer, polysorbate 80, povidone, propylene glycol, sodium carbonate, sodium lauryl sulfate, titanium dioxide, and triethyl citrate.

[0675] In another embodiment, the composition of formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') is provided in a effervescent dosage form. These effervescent dosage forms can further comprise non-release controlling excipients.

[0676] In another embodiment, the composition of formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') can be provided in a dosage form having at least one component that can facilitate immediate release of the active agent and at least one component that can facilitate controlled release of the active agent. In a further embodiment, the dosage form can be capable of providing discontinuous release of the compound in the form of at least two successive pulses separated in time by 0.1 to 24 hours. The composition can comprise one or more release controlling and non-release controlling excipients, such as those suitable for a rupturable semipermeable membrane and as swellable substances.

[0677] In another embodiment, the composition of formula (I), (la), (lb), (lc), (Id), (le), (II), (II'), (Ila), (III), or (III') is provided in a dosage form for oral administration to a subject in need thereof, comprising one or more pharmaceutically acceptable excipients or carriers, which are encapsulated in an intermediate reactive layer comprising a gastric fluid resistant polymeric layered material, which is partially neutralized with a base and has cation exchange capacity and an outer layer resistant to gastric fluids.

[0678] In some embodiments, the compositions of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') provided herein can be in unit dosage form or multiple dose form. Unit dosage form as used herein refers to physically discrete units suitable for administration to human subjects or non-human animal subjects and packaged individually. Each unit dose can contain a predetermined amount of active ingredient, sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carrier or excipient. Examples of unit dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. In some embodiments, the unit dosage form can be divided into several or multiple administrations. Multiple dose forms are multiple identical unit dosage forms packaged in a single container from which they can be administered in segregated unit dosage form. Examples of multiple dose forms include, but are not limited to, vials, bottles, or pint or gallon bottles filled with tablets or capsules. In another embodiment, the multiple dose form contains different pharmaceutically active agents.

[0679] In some embodiments, the compositions of Formula (I), (la), (lb), (Ic), (Id), (Ie), (II), (II'), (Ila), (III), or (III') can also be formulated into modified release dosage forms including immediate release, delayed release, prolonged release, extended release, sustained release, pulsed release, controlled release, prolonged, accelerated release and fasted release, targeted release, programmed release, and gastric residence dosage forms. These dosage forms can be prepared according to known methods and techniques (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126, which are incorporated herein by reference in their entirety).

[0680] Combination therapy

[0681] This article also relates to combination therapies, such as the co-administration of the disclosed compounds and additional therapeutic agents as part of a specific treatment regimen designed to provide a beneficial effect from the combined action of these therapeutic agents. The beneficial effect of such combination therapy includes, but is not limited to, the synergistic pharmacokinetic or pharmacodynamic effects resulting from the combination of therapeutic agents. The co-administration of these therapeutic agents is typically carried out over a defined time period (usually hours, days, weeks, months, or years, depending on the chosen combination). Combination therapies are intended to cover the sequential administration of multiple therapeutic agents, i.e., where the various therapeutic agents are administered at different times, and are also intended to cover the administration of these therapeutic agents or at least two therapeutic agents in a substantially simultaneous manner.

[0682] For example, substantially simultaneous administration is achieved by administering to a subject a single formulation or composition (e.g., tablets or capsules of various therapeutic agents in a fixed proportion) or multiple single formulations (e.g., capsules), each of which is administered simultaneously. The sequential or substantially simultaneous administration of the various therapeutic agents is achieved via any suitable route, including but not limited to oral, intravenous, intramuscular, and direct absorption through mucosal tissues. The therapeutic agents are administered via the same route or via different routes. For example, the first therapeutic agent in a selected combination is administered via intravenous injection, while the other therapeutic agents in the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally, or all therapeutic agents are administered via intravenous injection.

[0683] The components of the combination are administered to the patient simultaneously or sequentially. It should be understood that these components are contained in the same pharmaceutically acceptable carrier and therefore administered simultaneously. Alternatively, the active ingredient is contained in a separate pharmaceutical carrier, such as a conventional oral dosage form, for simultaneous or sequential administration.

[0684] In some embodiments, the compounds or salts of this disclosure may be administered in combination with oral corticosteroids. In some embodiments, the compounds or salts of this disclosure are administered in combination with deflazacort. In some embodiments, the compounds or salts of this disclosure are administered in combination with prednisone. In some embodiments, the compounds or salts of this disclosure are administered in combination with morpholino antisense oligomers. In some embodiments, the compounds or salts of this disclosure are administered in combination with exon skipping therapy. In some embodiments, the additional therapeutic agent is eteplirsen or atalulone.

[0685] In certain embodiments, the compounds or salts of the present disclosure are used in combination with gene therapy. In certain embodiments, the compounds or salts of the present disclosure are used in combination with an adeno-associated virus (AAV) comprising a gene encoding a replacement protein (e.g., dystrophin) or a truncated form thereof (e.g., microdystrophin). In certain embodiments, the compounds or salts of the present disclosure are administered in combination with vamorolone.

[0686] Examples

[0687] The present application will now be generally described with reference to the following examples, which are included for the purpose of illustration only and are not intended to limit the application in any way.

[0688] The following synthetic schemes are provided for illustration and not limitation. The following examples illustrate various methods of preparing the compounds described herein. It will be appreciated that those skilled in the art will be able to prepare these compounds by analogous methods or by making modifications known or to be developed to the methods known to those skilled in the art. It will also be appreciated that those skilled in the art will be able to prepare the compounds of the present disclosure by using appropriate starting materials and modifying the synthetic routes as described below in an analogous manner. In general, the starting materials and reagents can be obtained from commercial suppliers or synthesized or prepared as described herein or known to those skilled in the art.

[0689] Example 1. General Procedure - Synthesis of 2-benzyl-6-(2-(2,2,2- trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one

[0690]

[0691] Example 2. Exemplary Procedure - Synthesis of 2-benzyl-6-(2-(2,2,2- trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one

[0692]

[0693] The bromofluoropyrimidine is combined with an alcohol (e.g., 2,2,2-trifluoroethanol), cesium carbonate, and an aprotic solvent (e.g., DMF). If necessary, the mixture is gently heated to increase the rate of fluorine displacement. Isolation of the major product provides the corresponding 2-substituted pyrimidine. A Suzuki reaction at the C-4 bromo position using a palladium catalyst (e.g., [l,l-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a weak base (e.g., potassium acetate) in dioxane / water gives the biaryl core in good yield. Alkylation of the nitrogen is cleanly performed using various arylmethyl bromides or arylmethyl chlorides (e.g., benzyl chloride) and an inorganic base in a polar aprotic solvent (e.g., DMF). Alternatively, the nitrogen of the pyridinone can be functionalized using the Mitsunobu method. This requires a hydroxymethyl aryl compound (e.g., benzyl alcohol), triphenylphosphine, and a carbodiimide reagent (e.g., DEAD). Both alternatives are used to prepare the desired product depending on the availability of the appropriate coupling partner.

[0694] Examples 1 and 2 can be modified as appropriate to prepare the compounds described in Tables 1 and 2 herein.

[0695] Example 3: Synthesis of 2-(3-fluorobenzyl)-6-(4-(methylthio)phenyl)pyridazin-3(2H)-one

[0696]

[0697] Step 1 : 6-(4-(methylthio)phenyl)pyridazin-3(2H)-one

[0698] A mixture of 6-bromopyridazin-3(2H)-one (250 mg, 1.43 mmol), 4,4,5,5-tetramethyl-2-(4-(methylthio)phenyl)-l,3,2-dioxaborolane (357 mg, 1.43 mmol), Pd(dppf)Cl2(104.5 mg, 0.143 mmol), K2CO3(592 mg, 4.29 mmol) in dioxane (5.0 mL) / H2O (0.5 mL) was stirred at 90 °C for 4 h under N2atmosphere. The reaction was concentrated under vacuum to give a residue which was purified by silica gel chromatography (Flash 20 g, 30-80% EA:PE) to give the title compound (250 mg, 80.2%) as a yellow solid. LC / MS (ESI): 219 [M+H] + .

[0699] Step 2: 2-(3-fluorobenzyl)-6-(4-(methylthio)phenyl)pyridazin-3(2H)-one

[0700] To a stirred solution of 6-[4-(methylthio)phenyl]-2,3-dihydropyridazin-3-one (150 mg, 0.69 mmol) in DMF (2 mL) was added Cs2C03(672 mg, 2.06 mmol). Then 1-(bromomethyl)-3-fluorobenzene (143 mg, 0.76 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. The reaction was filtered and the filtrate was purified by preparative HPLC to give the title compound (100 mg, 44.6%) as a white solid. 1 H NMR (DMSO-d6, 300 MHz): δ 8.07 (d, J = 9.6 Hz, 1H), 7.86-7.81 (m, 2H), 7.44-7.34 (m, 3H), 7.20-7.08 (m, 4H), 5.34 (s, 2H), 2.56 (s, 3H); LC / MS (ESI): 327 [M+H] + .

[0701] Example 4: Synthesis of 2-(4-chlorobenzyl)-6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one

[0702]

[0703] Step 1 : 6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one

[0704] A mixture of 6-bromopyridazin-3(2H)-one (250 mg, 0.29 mmol), (2-fluoro-4- methoxyphenyl)boronic acid (267 mg, 0.31 mmol), K2C03(400 mg, 2.90 mmol) in dioxane (1.0 mL) / H20 (0.2 mL) was heated at 90 °C for 8 h under N2atmosphere. The reaction was concentrated under vacuum to give a residue which was purified by silica gel chromatography (Flash 20 g, 30-80% EA:PE) to give the title compound (150 mg, 76.3%) as a white solid. LC / MS (ESI): 221 [M+H] + .

[0705] Step 2: 2-(4-chlorobenzyl)-6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one

[0706] To a stirred solution of 6-(2-fluoro-4-methoxyphenyl)-2,3-dihydropyridazin-3-one (156 mg, 0.71 mmol) in DMF (2 mL) was added Cs2CO3(692 mg, 2.13 mmol). Then 1-(bromomethyl)-4-chlorobenzene (160 mg, 0.78 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. LCMS indicated the reaction went smoothly. The reaction was filtered and the filtrate was purified by prep-HPLC to give the title compound (32.1 mg, 13.1%) as a white solid. 1 HNMR (DMSO-d6, 300 MHz): δ 7.75 (dd, J1= 9.6 Hz, J2= 2.1 Hz, 1H), 7.59 (m, 1H), 7.43-7.36 (m, 4H), 7.07 (d, J = 9.6 Hz, 1H), 6.98 (dd, J1= 13.2 Hz, J2= 2.4 Hz, 1H), 6.92 (dd, J1= 8.7 Hz, J2= 2.4 Hz, 1H), 5.30 (s, 2H), 3.83 (s, 3H); LC / MS (ESI): 345 [M+H] + .

[0707] Example 5: Synthesis of N-(4-(l-(4-chlorobenzyl)-6-oxo-l,6-dihydro pyridazin-3- yl)phenyl)acetamide

[0708]

[0709] Step 1 : 6-bromo-2-(4-chlorobenzyl)pyridazin-3(2H)-one

[0710] To a stirred solution of 6-bromo-2,3-dihydropyridazin-3-one (600 mg, 3.43 mmol) in DMF (6 mL) was added Cs2CO3(3.35 g, 10.29 mmol). Then 1-(bromomethyl)-4- chlorobenzene (705 mg, 3.43 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. LCMS indicated the reaction went smoothly. The reaction was quenched by adding saturated aqueous NH4Cl (5 mL), then diluted with water (20 mL) and extracted with EA (25 mL) twice. The combined EA phase was washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. It was purified by silica gel chromatography (Flash 40 g, 20-30% EA:PE) to give the title compound (700 mg, 68.2%) as a white solid; LS / MS (ESI): 299

[0711] [M+H] + .

[0712] HNMR (DMSO-d6, 300 MHz): δ 7.75 (dd, J1= 9.6 Hz, J2= 2.1 Hz, 1H), 7.59 (m, 1H), 7.43-7.36 (m, 4H), 7.07 (d, J = 9.6 Hz, 1H), 6.98 (dd, J1= 13.2 Hz, J2= 2.4 Hz, 1H), 6.92 (dd, J1= 8.7 Hz, J2= 2.4 Hz, 1H), 5.30 (s, 2H), 3.83 (s, 3H); LC / MS (ESI): 345 [M+H]Step 2: N-(4-(l-(4-chlorobenzyl)-6-oxo-l,6-dihydropyridazin-3-yl)phenyl)acetamide

[0713] A mixture of 6-bromo-2-[(4-chlorophenyl)methyl]-2,3-dihydropyridazin-3-one (200 mg, 0.67 mmol), (4-acetamidophenyl)boronic acid (132 mg, 0.73 mmol), K2CO3(277 mg, 2.00 mmol) and Pd(dppf)Cl2(49 mg, 0.07 mmol) in dioxane (3 mL) containing H2O (0.2 mL) was stirred at 90 °C under N2atmosphere for 3 h. The reaction mixture was treated with silica gel column chromatography eluting with EA. The EA phase was then concentrated in vacuo to give the crude product which was purified by preparative HPLC to give the title compound (27.0 mg, 13.1%) as a white solid. 1 H NMR (DMSO-d6, 300 MHz): δ 10.14 (s, 1H), 8.05 (d, J = 9.9 Hz, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.44-7.37 (m, 4H), 7.08 (d, J = 9.6 Hz, 1H), 5.31 (s, 2H), 2.07 (s, 3H); LC / MS (ESI): 354 [M+H] + .

[0714] The following compounds were synthesized according to Example 5:

[0715]

[0716] Example 6: Synthesis of 2-[(4-chlorophenyl)methyl]-6-[2-(2,2,2- trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one

[0717]

[0718] Step 1 : 5-bromo-2-(2,2,2-trifluoroethoxy)pyrimidine

[0719] To a mixture of 5-bromo-2-chloropyrimidine (10 g, 0.021 mol, 1.0 eq) in DMSO (10 mL) was added 2,2,2-trifluoroethan-1-ol (6.21 g, 0.025 mol, 1.20 eq) and Cs2CO3(25.27 g, 0.062 mol, 3.0 eq) at room temperature. The reaction mixture was stirred at 70 °C for 2 h. The solution was diluted with water and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4and the solvent was removed under vacuum. Purification by silica gel chromatography (Flash 300 g, 0-40% EtOAc: cyclohexane) afforded the title compound (10.0 g, 94.08%) as a yellow oil. LC / MS (ESI): 257 [M+H] + .

[0720] Step 2: [2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]boronic acid

[0721] To a mixture of 5-bromo-2-(2,2,2-trifluoroethoxy)pyrimidine (5.0 g, 19.45 mmol, 1.0 eq) in dioxane (40 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan (7.41 g, 29.18 mmol, 1.5 eq), KOAc (5.73 g, 58.36 mmol, 3.0 eq) and Pd(dppf)Cl2(1.42 g, 1.94 mmol, 0.1 eq). The flask was purged and kept under a nitrogen inert atmosphere. The reaction mixture was stirred at 80 °C for 4 h and confirmed by LCMS. The reaction was used directly for the next step without workup.

[0722] Step 3: 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one

[0723] To a mixture of [2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]boronic acid (4.2 g, 18.93 mmol 1.0 eq) in dioxane (40 mL) was added 6-bromo-2,3-dihydropyridazin-3-one (3.31 g, 18.916 mmol, 1.00 eq), Pd(dppf)Cl2(0.69 g, 0.943 mmol, 0.05), K2CO3(3.92 g, 28.387 mmol, 1.5 eq) and H2O (4 mL). The flask was purged and kept under a nitrogen inert atmosphere. The resulting solution was stirred at 90 °C for 2 h. The solution was diluted with water and extracted with tOAc (30 mL x 3). The combined organics were washed with brine, dried over Na2SO4and the solvent was removed under vacuum. Purification by silica gel chromatography (Flash 300 g, 50-100% EtOAc: cyclohexane) afforded the title compound as a brown solid (3.0 g, 58.24%). LC / MS (ESI): 273 [M+H] + .

[0724] Step 4: 2-[(4-chlorophenyl)methyl]-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3- dihydropyridazin-3-one Step 1 : 6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one

[0725] To a mixture of 6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]-2,3-dihydropyridazin-3-one (1.0 g, 3.67 mmol, 1.0 eq) in DMF (10 mL) was added 1-(bromomethyl)-4-chlorobenzene (0.75 g, 0.004 mmol, 1.0 eq) and Cs2CO3(2.39 g, 0.007 mmol, 2.0 eq) at room temperature. The resulting solution was stirred at room temperature for 2 h. The residue was purified by preparative HPLC to give a white solid (700 mg, 48%). 1 H NMR (300 MHz, DMSO-d6): δ 9.16 (s, 2H), 8.13 (d, J = 9.9 Hz, 1H), 7.46-7.43 (m, 4H), 7.16 (d, J = 9.6 Hz, 1H), 5.33 (s, 2H), 5.12 (q, J = 9.0 Hz, 2H); LC / MS (ESI): 397 [M+H] + .

[0726] The following compounds were synthesized according to Example 6:

[0727]

[0728]

[0729]

[0730] Example 7: Synthesis of 2-(4-chlorobenzyl)-6-(2-fluoro-4-methoxyphenyl)pyridaz-3(2H)- one

[0731] Step 2: 2-(4-chlorobenzyl)-6-(2-fluoro-4-methoxyphenyl)pyridazin-3(2H)-one

[0732] A mixture of 6-bromopyridazin-3(2H)-one (250 mg, 0.29 mmol), (2-fluoro-4- methoxyphenyl)boronic acid (267 mg, 0.31 mmol), K2CO3(400 mg, 2.90 mmol) in dioxane (1.0 mL) / H2O (0.2 mL) was heated at 90 °C for 8 h under N2atmosphere. The reaction was concentrated under vacuum to give a residue which was purified by silica gel chromatography (Flash 20 g, 30-80% EA:PE) to give the title compound (150 mg, 76.3%) as a white solid. LC / MS (ESI): 221 [M+H] + .

[0733] Step 1 : 6-hydroxy-2-(l-phenylcyclopropyl)pyridazin-3(2H)-one

[0734] To a stirred solution of 6-(2-fluoro-4-methoxyphenyl)-2,3-dihydropyridazin-3-one (156 mg, 0.71 mmol) in DMF (2 mL) was added Cs2CO3(692 mg, 2.13 mmol). Then 1- (bromomethyl)-4-chlorobenzene (160 mg, 0.78 mmol) was added. The resulting mixture was stirred at 25 °C for 2 h. LCMS indicated the reaction went smoothly. The reaction was filtered and the filtrate was purified by prep-HPLC to give the title compound (32.1 mg, 13.1%) as a white solid. 1 HNMR (DMSO-d6, 300 MHz): δ 7.75 (dd, J1= 9.6 Hz, J2= 2.1 Hz, 1H), 7.59 (m, 1H), 7.43-7.36 (m, 4H), 7.07 (d, J = 9.6 Hz, 1H), 6.98 (dd, J1= 13.2 Hz, J2= 2.4 Hz, 1H), 6.92 (dd, J1= 8.7 Hz, J2= 2.4 Hz, 1H), 5.30 (s, 2H), 3.83 (s, 3H); LC / MS (ESI): 345 [M+H] + .

[0735] Example 8: Synthesis of 2-(1-phenylcyclopropyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5- yl)pyridazin-3(2H)-one

[0736]

[0737] Step 2: 6-bromo-2-(l-phenylcyclopropyl)pyridazin-3(2H)-one

[0738] To a mixture of (1-phenylcyclopropyl)hydrazine (400.00 mg, 2.699 mmol, 1.00 equiv) and maleic anhydride (291.11 mg, 2.969 mmol, 1.10 equiv) in H2O (1.60 mL) was added cone. HC1 (0.40 mL). The resulting solution was stirred at 95 °C for 8 h. The reaction was monitored by LCMS. After cooling to room temperature, the resulting mixture was concentrated in vacuo. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3). This resulted in 250 mg (40.58%) of 6-hydroxy-2-(1-phenylcyclopropyl)pyridazin-3(2H)-one as a solid.

[0739] Step 3: 2-(l-phenylcyclopropyl)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)- one

[0740] To a solution of 6-hydroxy-2-(1-phenylcyclopropyl)pyridazin-3-one (240.00 mg, 1.051 mmol, 1.00 equiv) in DCE (3.00 mL) was added phosphorous oxybromide (904.33 mg, 3.154 mmol, 3.00 equiv) portionwise. The resulting solution was stirred at 85 °C for 16 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1). This resulted in 200 mg (65.33%) of 6-bromo-2-(1-phenylcyclopropyl)pyridazin-3-one as a yellow solid.

[0741] Step 1 : 2-(phenylmethyl-d2)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)- one

[0742] The title compound was obtained as a white solid (84 mg, 31.5%) according to Example 8. 1 HNMR (300 MHz, DMSO-d6) δ 9.19 (s, 2H), 8.12 (d, J = 9.6 Hz, 1H), 7.33-7.14 (m, 3H), 7.13 (d, J = 9.9 Hz, 3H), 5.13 (q, J = 9.0 Hz, 2H), 1.67-1.54 (m, 4H). LC / MS Rt = 1.501 min, MS m / z: 389 [M+H] +

[0743] Example 9: Synthesis of 2-(phenylmethyl-d2)-6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridazin-3(2H)-one

[0744]

[0745] Animal

[0746] A mixture of 6-(2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl)pyridaz-3(2H)-one (100.00 mg, 0.367 mmol, 1.00 equiv), (bromomethyl-d2))benzene (63.58 mg, 0.367 mmol, 1.00 equiv), potassium carbonate (102.29 mg, 0.735 mmol, 2 equiv) in dimethylformamide (1.00 mL) was added to an 8 mL flask and stirred at 35 °C for 1 h. The mixture was purified by preparative HPLC (0.05% NH3H2O-H2O / CAN, 5% to 55% gradient, 30 min) to give 2-(phenylmethyl-d2)-6-(2-(2,2,2- trifluoroethoxy)pyrimidin-5-yl)pyridaz-3(2H)-one (80 mg, 59.77%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 2H), 8.55-8.53 (m, 2H), 8.15 (d, J = 9.9 Hz, 1H), 7.81-7.77 (m, 1H), 7.18 (d, J = 9.9 Hz, 1H). LC / MS Rt = 1.437 min; MS m / z: 386 [M+H] + .

[0747] Example 10. Skeletal muscle myofibril ATPase assay

[0748] Overview: Myosin ATPase activity is assessed by using a coupled reaction system in which ADP produced by myosin ATPase function is coupled to the disappearance of NADH by a pyruvate kinase / lactate dehydrogenase (PK-LDH) system. Myosin ATPase activity produces ADP, which is used as a substrate for PK to produce pyruvate and regenerate ATP. Pyruvate is then used as a substrate by LDH to oxidize NADH to NAD+. The rate of the reaction is monitored by the time-dependent disappearance of NADH using absorbance at 340 nm. Inhibition of ATPase activity by the compounds assayed is indicated by a decrease in the rate of NADH loss relative to vehicle-treated controls within the experimental time window. To assess the selectivity of the compounds assayed for skeletal muscle myofibrils, the compounds are counterscreened in cardiac myofibrils.

[0749] Materials: The following stock solutions and reagents are used in the skeletal muscle myofibril ATPase assay:

[0750]

[0751] Stock solution of pCa buffer. Combine PIPES, CaCl2, and EGTA solutions with 70 mL of water. Adjust the pH to 7.0 and adjust the final volume to 100 mL.

[0752]

[0753]

[0754] Buffer A and Buffer B. Buffers were stored on ice until use.

[0755] Buffer Preparation

[0756]

[0757] Skeletal muscle myofibril ATPase assay procedure: BSA, ATP, NADH, PEP, and DTT solutions were thawed at room temperature and then transferred to ice. Myofibrils were frozen pellets were transferred to a tube of sufficient size with approximately twice the desired volume and capped. Myofibrils were thawed by rolling in a water bath at room temperature for about 15 minutes and cooled on ice. Buffer A and B were prepared by adjusting the volume as needed according to the number of wells and stored on ice. 0.5 μL of the compound to be tested was added to the wells. 25 μL of Buffer A was dispensed into the wells, followed by 25 μL of Buffer B. The absorbance of the wells at 340 nm was measured using a kinetic protocol, where the wells were read every 1.5-2 minutes for 45 minutes. The slope of the data was approximated by subtracting the minimum absorbance value from the maximum value for each well. This was done in SoftMax Pro software or a spreadsheet program such as Excel. The data was normalized using GraphPad Prism 8.0 by assigning a value of 100% to the 1% DMSO vehicle well. Typically, the normalized 0% value was simply assigned to the (Max-Min) value 0. The normalized data was fit to a four-parameter Logistic sigmoidal equation with a floor constraint of 0 or greater. The compounds of Tables 1-4 were tested, and the results of the assays are presented in Table 5 herein. A = IC 50 Less than or equal to 10 μM; B = IC 50 Greater than 10 μM and less than 100 μM; C = IC 50 Greater than 100 μM.

[0758] Example 11. Cardiac myofibril ATPase assay

[0759] A counter screen was performed according to Example 10 using frozen myofibril pellets obtained from cardiac tissue. The assay was performed in the same manner as described above, but with the following notable differences: the final well concentration of myofibrils was 1.0 mg / mL, and KCl was omitted from the formulation.

[0760] The compounds of Tables 1-4 were tested, and the results of the assays are presented in Table 6 herein. A = IC 50 Less than or equal to 10 μM; B = IC 50greater than 10 μM and less than 100 μM; C = IC 50 greater than 100 μM; D = IC 50 greater than 60 μM.

[0761] Example 12. Tibialis Anterior Assay

[0762] Duchenne muscular dystrophy (DMD) patients and mdx mice lack dystrophin in their skeletal muscle and are more susceptible to contraction-induced injury than control muscle. The susceptibility of mdx mice to limb muscle injury after administration of the compounds disclosed herein was evaluated using in situ two piece maximally activated tibialis anterior (TA) muscle. A 20% stress segment relative to muscle fiber length was initiated from the plateau of isometric contraction. The degree of injury was assessed one minute later by the deficit in isometric force.

[0763] In situ preparation

[0764] Mice 2-19 months of age were tested. Specific pathogen free (SPF) C57BL controls and mdx mice were either purchased or bred in-house from a mating pair purchased from Jackson Laboratories. All control mice were of the C57BL / 10J strain except for the 19 month old mice which were C57BL / 6. The use of C57BL / 6 mice for the oldest group was necessary because unlike C57BL / 10J mice, C57BL / 6 mice can be purchased from the aging rodent colony maintained by the National Institute on Aging for high age mice.

[0765] Extended retraction protocol

[0766] Mice were initially anesthetized with an intraperitoneal injection of Avertin (tribromoethanol; 13-17 ll / g). Anesthesia was supplemented until no response to tactile stimulation was detected. This level of anesthesia was maintained throughout the experiment using additional doses of Avertin. The tendon of the TA was exposed through an incision at the ankle. The tendon was cut a few millimeters from the end of the muscle. The tendon was tied with 4.0 nylon suture as close to the muscle attachment as possible and the tendon was folded back on itself and tied again. The tendon and exposed muscle were kept moist by periodic application of isotonic saline. The mouse was placed on a heated platform maintained at 37°C. The mouse's foot was secured to the platform with a cloth tape and the knee was secured in a clamp between sharp screws. The tendon of the muscle was securely tied to the lever arm of a servo motor. The servo motor controlled the position of the muscle and monitored the force generated by the muscle. All data were displayed on a digital oscilloscope and stored on a computer.

[0767] The TA muscle was stimulated with 0.2-ms pulses through two needle electrodes that penetrated the skin on either side of the peroneal nerve near the knee. The stimulation voltage and subsequent muscle length (Lo) were adjusted for the maximum isometric twitch force (Pt). While held at Lo, the muscle was stimulated at increasing frequencies from 150 Hz in 50 Hz steps until the maximum force (Po) was reached, typically 250 Hz. A 1- to 2-minute rest period was allowed between each tetanic contraction. Muscle length was measured with a caliper based on well-defined anatomical landmarks near the knee and ankle. The optimal fiber length was determined by multiplying Lo by a TA Lf / Lo ratio of 0.6.

[0768] FIG. 1

[0769] Each muscle was stretched in situ twice, stimulating the muscle at 250 Hz, the frequency most often leading to Po. A protocol consisting of only two contractions was used to avoid fatigue. Stretching started from the plateau of the Lo tetanic contraction. The time course of the protocol is shown in FIGS. 3-6 At time 0, stimulation was started, and the muscle was held motionless for 100 ms to allow maximum activation. From the plateau of the maximum isometric contraction, a length change (LC1) of 20% Lf was applied at a rate of 1 Lf / s. Stimulation was stopped at the end of the stretch ramp. The muscle was held at the stretched length for 100 ms and then returned to Lo at the same rate. The same second lengthened contraction (LC2) as the first was performed 10 minutes later. The maximum isometric force was measured 1 minute later and again every 5 minutes for 15 minutes. Force deficit was calculated as the difference between the isometric force during LC1 and the maximum isometric force measured at any given time and expressed as a percentage of the isometric force during LC1. Recovery within 15 minutes after the two lengthened contraction protocol was quantified as the difference between the isometric force measured at 15 minutes and the isometric force after the second lengthened contraction and expressed as a percentage of the initial Po.

[0770] The experimental protocol included two muscle stretches during maximal activation followed by maximal activation to measure the reduction in maximal isometric force (Po). The change in muscle length is shown relative to the fiber length (Lf) at 20% stress, where 100% corresponds to the optimal muscle length for force development (Lo). The muscle was stretched at a rate of 2 Lf / s. The reduction in Po after the two stretch protocol in a representative mdx mouse is shown. Each lengthened contraction started from the plateau of the maximal isometric contraction. The second lengthened contraction (LC2) occurred 10 minutes after the first lengthened contraction (LC1). The maximal force during the isometric contraction was measured 10 minutes after LC2 (tl min). The force deficit was calculated by dividing the difference between Po during LC1 and Po measured at any time after LC1 by the Po during LC1 and multiplying by 100%. The suture was cut from the muscle and the muscle was weighed. After removal of the TA muscle, the deeply anesthetized mouse was euthanized by inducing a pneumothorax. The total cross-sectional area (CSA) of muscle fibers of the TA muscle was calculated by dividing the muscle mass by the product of Lf and 1.06 mg / mm3(density of mammalian skeletal muscle). The specific Po was calculated by dividing Po by CSA. The results of the test are shown in FIG. 3 .

[0771] FIG. 4 The reduction in force before injury at 100 Hz for compound 5 of the disclosure is shown. Force in the TA muscle of an mdx mouse was measured in situ at 100 Hz before and after oral administration of compound 5. A 100 Hz stimulus was applied every 10 minutes and the change in force was recorded before the start of the centrifugation injury protocol. This measure gives an indication of the relative ability of compound 5 to reduce force in the target tissue.

[0772] FIG. 5 The reduction in force after injury at 175 Hz for compound 5 of the disclosure is shown. The maximal force was measured in situ in the TA muscle at 175 Hz before and 10 minutes after the two rounds of lengthened (lengthened) contractions. In mdx mice, lengthened contractions produce exaggerated force drop. This measure gives an indication of the relative ability of compound 5 to reduce the drop in force after centrifugation contractions. FIG. 6 The intermediate lengthened force drop for compound 5 of the disclosure is shown. The TA muscle was injured in situ by two maximal centrifugation contractions, each 20% lengthened, 10 minutes apart. This indicator measures the relative drop in pre-lengthened force between the first and second contractions.

[0773] FIG. 1 The increase in TA mass after injury for compound 5 of the disclosure is shown.

[0774] Prolonged injury to TA muscle in mdx mice results in a delayed increase in muscle weight after injury. This can be due to fluid accumulation in the form of edema. Muscles were removed from mice (both injured and contralateral) 1 hour after injury and weighed. The relative increase in weight of the injured muscle relative to the contralateral muscle was recorded. A decrease in this relative change indicates a decrease in edema after injury.

[0775] In some embodiments, the compounds of the present disclosure are as shown in Table 1 below.

[0776] Table 1

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788] In some embodiments, the compounds of the present disclosure are as described in Table 2 below.

[0789] Table 2

[0790]

[0791]

[0792]

[0793]

[0794]

[0795] In certain embodiments, the compounds of the methods described herein can be selected from commercially available compounds, including those depicted in Table 3. The compounds of Tables 3 and 4 were tested, and the results of the assays are presented in Table 6 herein. A = IC50 less than or equal to 10 μΜ; B = IC 50 greater than 10 μΜ and less than 100 μΜ; C = IC 50 greater than 100 μΜ.

[0796] Table 3

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806] In certain embodiments, other compounds of the methods described herein include those in Table 4, or salts thereof.

[0807] Table 4

[0808]

[0809]

[0810]

[0811]

[0812] The compounds of the present disclosure have bone IC values shown in Table 5 50 Values.

[0813] Table 5

[0814]

[0815]

[0816]

[0817] A = IC 50 less than or equal to 10 μΜ; B = IC 50 greater than 10 μΜ and less than 100 μΜ; C = IC50 greater than 100 μM.

[0818] The compounds of the present disclosure have cardiac IC 50 values as in Table 6.

[0819] Table 6

[0820]

[0821]

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein said compound has the structure of formula (I): in: each X is independently selected from C(R 3 ) and N, wherein at least one X is N; A is selected from -O- and -NR 4 -; R 1 selected from the group consisting of: C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 aromatic, carbocyclic, and 3- to 10-membered heterocyclic ring, wherein said C 3-10 aromatic, carbocyclic, and 3- to 10-membered heterocyclic ring is optionally substituted with one or more R 9 ; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; or R 1 with R 3 together form a 5- to 10-membered heterocyclic ring, wherein the 5- to 10-membered heterocyclic ring is optionally substituted with one or more R 9 ; and when A is -NR 4 -; R 1 is additionally selected from hydrogen; each R is independently selected from the group consisting of: 2 is independently selected from the group consisting of: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and C 1-3 alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; R 3 selected from the group consisting of: hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 3 with R 1 together form a 5- to 10-membered heterocyclic ring, wherein the 5- to 10-membered heterocyclic ring is optionally substituted with one or more R 9 ; R 4 are independently selected from: Hydrogen; and C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; or R 4 with R 1 together form a 3- to 10-membered heterocyclic ring, which is optionally substituted by one or more R 9 ; each R is independently selected from the group consisting of: 9 is independently selected from the group consisting of: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and C 1-3 alkyl, C 2-3 alkenyl and C 2-3 alkynyl, each of which is optionally substituted with one or more substituents independently selected from halo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; each R is independently selected from the group consisting of: 10 is independently selected from the group consisting of: hydrogen; C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle and 3- to 10-membered heterocycle; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and haloalkyl; n is 0; p is 0; and q is 0, 1, 2, 3, 4, or 5, provided that when q is 0, R 1 is not -CH3.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is represented by formula (Ia) or formula (Ib):

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is represented by formula (Ia):

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is represented by formula (Ic) or formula (Id):

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is represented by Formula (Ic):

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein A is -O-.

7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is -NR 4 - 8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 aromatic, carbocyclic, and 3- to 10-membered heterocyclic ring, wherein each said C 3-10 aromatic, carbocyclic, and 3- to 10-membered heterocyclic ring is optionally substituted with one or more R 9 .

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =0, =S, =N(R 10 ), -CN, C 3-10 carbocycle and 3- to 10-membered heterocycle, wherein said C 3-10 carbocycle and 3- to 10-membered heterocycle are each optionally substituted with one or more R 9 .

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OR 10 and C 9 3- to 6-membered heterocycle optionally substituted with one or more R 9 substituents independently selected from halogen, -OR 3-5 substituents independently selected from halogen, -OR 11. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl optionally substituted with one or more groups independently selected from halogen, -OR 10 and C 9 3- to 6-membered heterocycle optionally substituted with one or more R 9 substituted with one or more R 3-5 substituted with one or more R 9 substituted with one or more R 1-3 alkyl, C 1-3 haloalkyl, and halogen.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -CH3, -CF3, -CH2F, -CHF2, -CH2CHF2, -CH2CF3, -C(=O)CH3, 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from -CF3, -CHF2, and -CH2CF3.

14. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen.

15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from C 3-10 Carbon rings and 3 to 10-membered heterocycles, wherein each is optionally selected independently by one or more halogens, -OR 10 -SR 10 -N(R) 10 )2、-C(O)R 10 -C(O)N(R) 10 )2、-N(R 10 )C(O)R 10 -N(R) 10 )C(O)N(R 10 )2、-OC(O)N(R 10 )2、-N(R 10 )C(O)OR 10 -C(O)OR 10 -OC(O)R 10 -S(O)R 10 -S(O)2R 10 , -NO2, =O, =S, =N(R 10 Substituents of -CN and -CN are used.

16. The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3-10 carbon ring optionally substituted with one or more substituents independently selected from the group consisting of halogen, -CN, -OH, -SH, -NO2, -NH2, =0, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbon ring, 3- to 10-membered heterocycle, and haloalkyl.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from optionally substituted C3cycloalkyl.

18. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from optionally substituted C4-C6cycloalkyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R 1 selected from 20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 together with R 3 form a 5- to 10-membered heterocycle, wherein the 5- to 10-membered heterocycle is optionally substituted with one or more R 9 .

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 together with R 4 form a 3- to 10-membered heterocycle, wherein the 3- to 10-membered heterocycle is optionally substituted with one or more R 9 .

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein the 3- to 10-membered heterocycle formed together with R 1 and R 4 is selected from 4-, 5-, 6-, or 7-membered rings, any of which is optionally substituted with one or more R 9 .

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein the 3- to 10-membered heterocycle formed together with R 1 together with R 4 is selected from: wherein any one is optionally substituted with one or more R 9 .

24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein the 3- to 10-membered heterocycle formed together with R 1 and R 4 together form a 3- to 10-membered heterocycle selected from:

25. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from halogen, -OH, -SH, -NH2, -NO2, -CN, and C 1-3 alkyl optionally substituted with one or more substituents independently selected from halogen, -OH, -SH, -NH2, -NO2, and -CN.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently selected from the group consisting of: -Cl, -F, and -Br.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein each R 2 is -Cl.

28. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

30. Use of compounds of formula (III) or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment and / or prevention of neuromuscular disorders or movement disorders: in: each Y is independently selected from C(R 3 ) and N; At least one of Y is N; A is selected from -O- and -NR 4 -; R 1 selected from the group consisting of: C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), -CN, C 3-10 aromatic and heteroaromatic rings, carbocyclic and 3- to 10-membered heterocyclic rings, wherein each said C 3-10 aromatic and heteroaromatic rings, carbocyclic and 3- to 10-membered heterocyclic rings is optionally substituted with one or more R 9 ; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; or R 1 with R 3 together form a 5- to 10-membered heterocyclic ring, wherein the 5- to 10-membered heterocyclic ring is optionally substituted with one or more R 9 ; and when A is -NR 4 -; R 1 is additionally selected from hydrogen; each R is independently selected from the group consisting of: 2 is independently selected from the group consisting of: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and C 1-3 alkyl, optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, =0, =S, =N(R 10 ), and -CN; each R is independently selected from the group consisting of: 3 selected from the group consisting of: hydrogen, halogen, -OR 10 , -SR 10 , -N(R 10 )2, -NO2, and -CN; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 3 with R 1 together form a 5- to 10-membered heterocyclic ring, wherein the 5- to 10-membered heterocyclic ring is optionally substituted with one or more R 9 ; R 4 are independently selected from the group consisting of: Hydrogen; and C 1-6 Alkyl group, optionally composed of one or more elements independently selected from halogens, -OR 10 -SR 10 -N(R) 10 )2, replaced by substituents of -NO2 and -CN; or R 4 with R 1 together form a 3- to 10-membered heterocyclic ring, which is optionally substituted by one or more R 9 ; each R is independently selected from the group consisting of: 9 is independently selected from the group consisting of: halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ), and -CN; and C 1-3 alkyl, C 2-3 alkenyl and C 2-3 alkynyl, wherein each is optionally substituted with one or more substituents independently selected from halo, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 , -N(R 10 )C(O)N(R 10 )2, -OC(O)N(R 10 )2, -N(R 10 )C(O)OR 10 , -C(O)OR 10 , -OC(O)R 10 , -S(O)R 10 , -S(O)2R 10 , -NO2, =O, =S, =N(R 10 ) and -CN; each R is independently selected from the group consisting of: 10 is independently selected from the group consisting of: hydrogen; C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of halo, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 3-10 carbocycle and 3- to 10-membered heterocycle; and C 3-10 carbocycle and 3- to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -CN, -OH, -SH, -NO2, -NH2, =O, =S, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -N(C 1-6 alkyl)2, -NH(C 1-6 alkyl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocycle, 3- to 10-membered heterocycle, and C 1-6 haloalkyl; R 30 and R 31 is independently hydrogen; n is 0; p is 0; and q is 0, 1, 2, 3, 4, or 5. The neuromuscular disorders mentioned therein are selected from Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy type 1, myotonic dystrophy type 2, facial-scapular-humeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb girdle muscular dystrophy, tendinitis, and carpal tunnel syndrome; and the movement disorder mentioned therein is muscle spasm.

31. Use of any compound of claims 1 to 29 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prevention of neuromuscular disorders or movement disorders, wherein the neuromuscular disorder is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy type 1, myotonic dystrophy type 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb girdle muscular dystrophy, tendinitis, and carpal tunnel syndrome; and wherein the movement disorder is muscle spasticity.

32. Use of any compound of claims 1 to 29 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment and / or prophylactic inhibition of myosin II.

33. The use according to claim 30 or 31, wherein the neuromuscular disease is Duchenne muscular dystrophy.

34. Use of any compound of claims 1-29 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing movement disorders, wherein the movement disorder is muscle spasm, and wherein the muscle spasm is selected from spasms associated with multiple sclerosis, Parkinson's disease, Alzheimer's disease, cerebral palsy, stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, and amyotrophic lateral sclerosis.

35. A pharmaceutical composition comprising a compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

36. The use of claim 30, 31, 32, or 34, wherein the medicament comprises an additional therapeutic agent.

37. The use of claim 36, wherein the additional therapeutic agent is a corticosteroid.

38. The use of claim 37, wherein the corticosteroid is deflazacort or prednisone.

39. The use of claim 36, wherein the additional therapeutic agent is vamorolone.

40. The use of claim 36, wherein the additional therapeutic agent is a gene therapy.

41. The use of claim 40, wherein the gene therapy is a gene therapy employing a dystrophin gene or a variant or truncated form thereof.

42. The use of claim 40, wherein the gene therapy is a gene therapy employing microdystrophin.

43. The use of claim 36, wherein the additional therapeutic agent is eteplirsen.

44. The use of claim 36, wherein the additional therapeutic agent is ataluren.

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